NZ624040B2 - 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh - Google Patents

3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh Download PDF

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NZ624040B2
NZ624040B2 NZ624040A NZ62404012A NZ624040B2 NZ 624040 B2 NZ624040 B2 NZ 624040B2 NZ 624040 A NZ624040 A NZ 624040A NZ 62404012 A NZ62404012 A NZ 62404012A NZ 624040 B2 NZ624040 B2 NZ 624040B2
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optionally substituted
mmol
alkyl
phenyl
group
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NZ624040A
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NZ624040A (en
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Thomas CAFERRO
Young Shin Cho
Abran Q Costales
Huangshu Lei
Francois Lenoir
Julian Roy Levell
Gang Liu
Mark G Palermo
Keith Bruce Pfister
Martin Sendzik
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Novartis Ag
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Priority claimed from PCT/IB2012/055133 external-priority patent/WO2013046136A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

Disclosed are 3-pyrimidin-4-yl-oxazolidin-2-one compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-R6 are defined in the specification. Also disclosed are compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. Further disclosed is the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer. H proteins having a neomorphic activity. Further disclosed is the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

Description

-PYRIMIDINYL-OXAZOLIDINONES AS INHIBITORS OF MUTANT IDH FIELD OF THE INVENTION The t invention is directed to novel 3-pyrimidinylyl-oxazolidinone compounds, compositions containing these nds, the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic ty and in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
BACKGROUND OF THE INVENTION Isocitrate dehydrogenase (IDH) is a key family of enzymes found in cellular metabolism. They are NADP+ / NAD+ and metal dependent oxidoreductases of the enzyme class EC 1.1.1.42. The wild type ns catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate generating carbon dioxide and NADPH / NADH in the process. They are also known to convert oxalosuccinate into alpha-ketoglutarate.
Mutations in IDH1 (cytosolic) and IDH2 (mitochondrial) have been identified in multiple cancer types including, but not limited to, glioma, astoma multiforme, paraganglioma, supratentorial primordial neuroectodermal , acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma. (See L. Deng et al., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J. Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010; Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol., 2008). The mutations have been found at or near key residues in the active site: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 and R172 for IDH2. (See L. Deng et al., Nature, 2009, 462, 739; L. Sellner et al., Eur. J. Haematol., 2011, 85, 457).
These mutant forms of IDH are shown to have a neomorphic activity (also known as a gain of function activity), ng alpha-ketoglutarate to 2-hydroxyglutarate .
(See P.S. Ward et al., Cancer Cell, 2010, 17, 225) In general, tion of 2-HG is enantiospecific, resulting in tion of the D-enantiomer (also known as R enantiomer or RHG). Normal cells have low native levels of 2-HG, whereas cells ing these mutations in IDH1 or IDH2 show significantly elevated levels of 2-HG. High levels of 2- HG have been detected in tumors harboring the mutations. For example, high levels of 2- HG have been detected in the plasma of patients with mutant IDH containing AML. (See 8. Gross et al., J. Exp. Med., 2010, 207(2), 339). High levels of 2-HG are highly associated with tumorigenesis. 2012/055133 Mutant IDH2 is also ated with the rare neurometabolic disorder D hydroxyglutaric ia type II (DHGA type II). Germline mutations were found at R140 in IDH2 in 15 ts having DHGA type II. Patients having this disorder also have consistently increased levels of DHG in their urine, plasma and cerebrospinal fluid. (See Kranendijk, M. et al., Science, 2010, 330, 336). Finally, patients with Ollier Disease and i me (two rare disorders that predispose to cartilaginous tumors) have been shown to be somatically mosaic for IDH1 and 2 mutations and exhibit high levels of DHG. (See Amary et al., Nature Genetics , 2011 and Pansuriya et al., Nature Genetics, 2011).
Thus, there is a need for small molecule inhibitors of mutant IDH proteins having a neomorphic activity for the treatment of diseases and disorders associated with these SUMMARY OF THE INVENTION In one aspect, this invention provides for a compound of formula (I) NI \ o X / A HN N N or a pharmaceutically acceptable salt thereof, wherein R1-R6 are defined .
In a second aspect, this invention provides for a pharmaceutical ition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a ceutically acceptable carrier or excipient.
In a third aspect, this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of a mutant IDH protein having a neomorphic activity such as reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphic activity). Suitably, this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of mutant IDH1 having a neomorphic activity, such as 2-HG neomorphic activity, and/or mutant IDH2 having a neomorphic activity, such as 2-HG neomorphic activity. This ion further provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example 697D, R100Q, R132H, R132C, R1328, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R1728, R172G, and R172W.
In a fourth aspect, this invention provides for a method of treating a e or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of an effective amount of a compound according to a (I), or a pharmaceutically able salt thereof, to a subject in need thereof. In one embodiment, the e or disorder is a cell proliferation disorder, such as cancer. In another ment, the cancer is brain cancer, such as glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (pNET); leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome, and c myelogenous leukemia (CML); skin cancer, including melanoma; prostate cancer; thyroid cancer; colon cancer; lung cancer; sarcoma, ing central chondrosarcoma, central and teal chondroma; and fibrosarcoma. In r embodiment the disease or disorder is Dhydroxyglutaric aciduria.
In a fifth aspect the invention provides for a compound of formula (I), or a ceutically acceptable salt thereof, in combination with another therapeutic agent.
These and other aspects of the present invention are described r in the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a compound of a (I) A compound of formula (I) NI \ o X / A HN N N wherein: R1 and R2 are each independently hydrogen, deuterium, halo, hydroxyl, NH2, aryl, heteroaryl, or optionally substituted C1_4 alkyl, wherein said C1_4 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, and NH2; R38' is hydrogen, deuterium, 01-6 alkyl, phenyl, or benzyl and R3b is en, deuterium, or 01-6 alkyl; or R33 and R3b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally tuted 4-7 membered heterocyclic ring, wherein said lkyl and heterocyclic rings are each optionally tuted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and C1_3 alkyl; R48' is hydrogen, 01-6 alkyl, optionally substituted , optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene, wherein said , benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_4 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, -COORb, -802Rb, -NHC(O)Rb, and -NRbRb and R4b is hydrogen, deuterium, or C1_3 alkyl; or R48' and R4b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring, wherein said cycloalkyl and heterocyclic rings are optionally substituted with one or two tuents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and C1_3 alkyl, ed that only one of R33 and R3b and R48' and R4b are joined together forming a ring; R58' is en or ium; R5b is hydrogen, deuterium, methyl, ethyl, CD3, CF3, CH2F, or CHF2 and R6 is optionally substituted 01-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted 03-10 cycloalkyl, wherein said 01-6 alkyl is optionally substituted with one substituent selected from the group consisting of hydroxyl, 01-3 alkoxy and —ORa, wherein said aryl, heteroaryl, heterocyclic and 03-10 cycloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo; hydroxyl; cyano; nitro; 01-4 alkoxy; 01-3 haloalkyl; 01-3 koxy; 01-6 alkyl; 03-6 cyc|oa|ky| optionally substituted with one to three substituents each ndently selected from the group consisting of: hydroxyl, cyano, 01-3 alkyl, 01-3 alkoxy, and 01-3 haloalkyl; phenyl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 koxy, 01-6 alkyl, 03-6 cyc|oa|ky|, 5-6 membered heteroaryl, 5-6 ed heterocyclic, phenoxy, -COORb, -802Rb, -NHO(O)Rb, and —NRbRb; 5-6 membered heteroaryl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, 01-3 alkyl, 01-3 alkoxy; 5-6 membered heterocyclic optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl; -0H2Ra; -ORa; a; -NRaRb; -COORa; —802Ra; —sosz; NHO(O)Ra; -NHO(O)Rb; —0(O)NRaRb; -0(O)NHRb; and -SOZNRbRb; or R5b and R6 are joined together forming an optionally substituted 03-7 cyc|oa|ky| group or an optionally tuted group of formula (a): (a), wherein n is 1, 2, or 3 and said 03-7 cyc|oa|ky| and group of formula (a) are optionally tuted with one to three tuents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cyc|oa|ky|, 5-6 membered aryl, 5-6 ed heterocyclic, benzyloxy, -COORb, —sosz, -NHO(O)Rb, and -NRbRb; each R8 is independently optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, or ally substituted 03-7 cyc|oa|ky|, wherein said phenyl and heteroaryl are optionally substituted with one to three substituents each independently ed from the group consisting of halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, and 01-3 alkyl, wherein said heterocyclic is optionally tuted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, 01-3 alkoxy, 01-3 hanaIkyI, 01-3 haloalkoxy, C1_4 aIkyI, 03-5 cycIoaIkyI, b, and —NRbRb; and wherein said 03-7 cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, and 01-3 alkyl; and each Rb is independently hydrogen or 01-6 alkyl.
“Alkyl” refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms. For example, 01-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted with one or more substituents as defined in a (I). Alkyl groups may be straight or branched.
Representative branched alkyl groups have one, two, or three branches. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyI, isobutyl, sec-butyl, and t-butyI), pentyl (n-pentyI, isopentyl, and neopentyl), and hexyl.
“AIkoxy” refers to any alkyl moiety attached h an oxygen bridge (Le. a —0- 01-3 alkyl group wherein 01-3 aIkyI is as defined ). Examples of such groups include, but are not limited to, y, ethoxy, and y.
“Aryl” refers to a hydrocarbon ring system having an aromatic ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl rings refer to naphthyl and to rings wherein phenyl is fused to a C5- 7 cycloalkyl or 05.7 cycloalkenyl ring as defined herein. Aryl groups may be optionally substituted with one or more substituents as defined in formula (I). alkyl” refers to a saturated hydrocarbon ring system having the specified number of carbon atoms. Cycloalkyl groups are monocyclic or bicyclic ring s. For example, 05-10 cycIoaIkyI refers to a cycIoaIkyI group having from 5 to 10 carbon atoms.
Cycloalkyl groups may be optionally substituted with one or more substituents as defined in formula (I). Examples of cycIoaIkyI groups include, but are not d to, cycIopropyI, cycIobutyI, cycIopentyI, cycIohexyI, cycIoheptyI, and adamantanyI.
“Cycloalkenyl” refers to an unsaturated hydrocarbon ring system having the specified number of carbon atoms and having a carbon-carbon double bond within the ring. For example, C5_7 cycloalkenyl refers to a cycloalkenyl group having from 5 to 7 carbon atoms. In certain ments, cycloalkenyl groups have one carbon-carbon double bond within the ring. In other ments, cycIoaIkeneyI groups have more than one carbon-carbon double bond within the ring. Cycloalkenyl rings are not aromatic. lkenyl groups may be optionally substituted with one or more substituents as defined in formula (I).
“Halo” refers to the halogen radicals fluoro, chloro, bromo, and iodo.
“Haloalkyl” refers to an alkyl group wherein at least one hydrogen atom attached to a carbon atom within the alkyl group is replaced with halo. The number of halo substituents includes, but is not d to, 1, 2, 3, 4, 5, or 6 substituents. kyl includes, but is not d to, monofluoromethyl, difluoroethyl, and trifluoromethyl.
“Haloalkoxy” refers to a haloalkyl moiety attached through an oxygen bridge (Le. a —O-C1_3 haloalkyl group wherein 01-3 haloalkyl is as defined herein). An example ofa haloalkoxy group is trifluoromethoxy.
“Heteroaryl” refers to an aromatic ring system containing from 1 to 5 heteroatoms.
Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups are clic ring systems or are fused ic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms.
Bicyclic aryl rings have from 8 to 10 member atoms. Bicyclic heteroaryl rings include those ring systems wherein a heteroaryl ring is fused to a phenyl ring. Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), lyl, isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3-, and 4- nyl), dinyl, pyridazinyl, pyrazinyl, trazinyl, inyl, tetrzolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, naphthyridinyl, 1H- pyrrolo[2,3-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl and the like.
“Heteroatom” refers to a nitrogen, oxygen, or sulfur atom.
“Heterocyclic” refers to a 3 to 11 membered ted or unsaturated monocyclic or ic ring containing from 1 to 4 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain ent heteroatoms. Heterocyclic includes ring systems wherein a sulfur atom is oxidized to form 80 or 802. Heterocyclic groups may be optionally substituted with one or more tuents as d in formula (I). Heterocyclic groups are monocyclic, spiro, or fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings have 3 to 7 ring atoms. Examples of monocyclic heterocyclic groups include oxtanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3- dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, ydropyranyl, opyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, thianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran1,1-dioxide, 1,4-diazepanyl, and the like. Fused heterocyclic ring systems have from 8 to 11 ring atoms and include groups wherein a heterocyclic ring is fused to a phenyl ring, a heteroaryl ring or another heterocyclic ring.
Examples of fused cyclic rings include 2,3-dihydrobenzo[b][1,4]dioxinyl, octahydro— pyrrolo[1,2-a]pyrazinyl, dro-pyrido[1,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, ,6,7,8—tetrahydro—[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8—tetrahydro-imidazo[1,2- a]pyrazinyl and the like. Examples of bridged heterocyclic groups include 3,8—diaza- o[3.2.1]octanyl, aza-bicyclo[4.2.0]octanyl and the like. Examples of spiro heterocyclic groups include 4,7-diaza-spiro[2.5]octanyl and the like. “4-7 membered heterocyclic” refers to a heterocyclic group as defined above, having from 4 to 7 ring atoms and containing from 1 to 4 heteroatoms. “5-6 membered heterocylic” refers to a heterocyclic group as d above, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.
“Optionally substituted” tes that a group, such as an alkyl, cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may be unsubstitued or the group may be substituted with one or more substituents as defined in formula (I).
“Oxo” refers to a C=O group.
“Pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of compounds of the invention which are suitable for use in medicine are those where in the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
“Substituted” in reference to a group such as alkyl, phenyl, benzyl, heteroaryl, and heterocyclic, indicates that one or more hydrogen atoms attached to an atom within the group is ed with a substituent selected from the group of defined substituents.
It should be tood that the term “substituted” includes the it provision that such tution be in accordance with permitted e of the substituted atom and the substituent, and that the tution results in a stable compound (i.e. one that does not spontaneously undergo transformation, for example, by hydrolysis, rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) atoms within the group may be substituted. In addition, a single atom within the group may be substituted with more than one substituent as long as such substitution is accordance with the permitted valence of the atom. Suitable substituents are defined for each tuted or optionally substituted group.
The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to formula (I) may be prepared. These salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, , oxalate, palmitate, pamoate, ate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, te, tosylate and trifluoroacetate salts. lnorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. c acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns | to XII of the periodic table. In certain embodiments, the salts are derived from , potassium, ammonium, m, magnesium, iron, silver, zinc, and copper; particularly suitable salts include um, potassium, , calcium and magnesium salts.
Organic bases from which salts can be derived include, for e, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic , basic ion exchange resins, and the like. Certain c amines e pylamine, hine, cholinate, diethanolamine, diethylamine, , ine, piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such ons are typically carried out in water or in an c solvent, or in a mixture of the two.
Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional le salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Solvates, including pharmaceutically acceptable solvates, of the compounds of formula (I) may also be prepared. “Solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not d to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric s of water, as well as compositions containing variable amounts of water.
The compounds of a (I), including salts and solvates f, may exist in crystalline forms, non-crystalline forms, or mixtures f. The compound or salt or solvate thereof may also exhibit polymorphism, i.e. the capacity of occurring in different crystalline forms. These ent crystalline forms are typically known as orphs”.
Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of lline solid state. Polymorphs, ore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X—ray powder diffraction patterns, all of which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing a compound of formula (I).
The invention also includes various s of the compounds of formula (I). “lsomer” refers to nds that have the same composition and lar weight but differ in physical and/or chemical ties. The structural difference may be in tution (geometric isomers) or in the ability to rotate the plane of polarized light (stereosiomers). With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present ion, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted lkyl, the cycloalkyl substituent may have a cis- or trans- configuration. All tautomeric forms are also intended to be included.
Any asymmetric atom (e.g., carbon or the like) of a compound of formula (I) can be present in racemic or enantiomerically enriched, for example the (R)—, (S)— or (R,S)— configuration. In certain ments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)— or (8)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)— or trans— (E)— form. ingly, as used herein a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for e, as substantially pure ric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or es thereof.
Any resulting mixtures of isomers can be separated on the basis of the ochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the reomeric salts thereof, ed with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the t invention into their l des, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0’-p—toluoyl tartaric acid, mandelic acid, malic acid or r—10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
The invention includes unlabeled forms as well as isotopically labeled forms of compounds of formula (I). ically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include es of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 358, 36Cl, 125l respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such ically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission aphy (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in ctive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. lsotopically-labeled compounds of formula (I) can lly be prepared by conventional techniques known to those skilled in the art or by processes analogous to those bed in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed.
Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from r metabolic stability, for example sed in vivo half-life or d dosage ements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a r isotope, specifically deuterium, may be defined by the isotopic enrichment factor.
The term "isotopic ment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an ic ment factor for each designated ium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% ium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Representative ments Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide for further embodiments.
One embodiment of the present invention is a compound according to formula (I) wherein: each R1 and R2 is independently hydrogen, deuterium, halo, hydroxyl, NH2, aryl, heteroaryl, or optionally tuted C1_4 alkyl, wherein said C1_4 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, and NH2; R38' is hydrogen, deuterium, 01-6 alkyl, phenyl, or benzyl and R3b is en, deuterium, or 01-6 alkyl; or R33 and R3b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring, wherein said cycloalkyl and cyclic rings are optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl; R48' is en, 01-6 alkyl, optionally substituted phenyl, optionally tuted benzyl, ally substituted heteroaryl, or methylene-dibenzene, wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, yl, cyano, nitro, C1_3 alkoxy, C1_3 haloalkyl, C1_3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COORb, sosz, NHC(O)Rb, and NRbRb and R4b is hydrogen, deuterium, or 01-3 alkyl; or R48 and R4b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 ed heterocyclic ring, n said cycloalkyl and heterocyclic rings are optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl, provided that only one of R38' and R3b and R48' and R4b are joined together forming a ring; R58 is hydrogen or deuterium; R5b is hydrogen, ium, methyl, ethyl, CD3, CF3, CH2F, or CHF2 and R6 is optionally substituted 01-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclic, or optionally substituted 05-10 cycloalkyl, wherein said 01-6 alkyl is optionally substituted with one substituent selected from the group consisting of hydroxyl, 01-3 alkoxy and —ORa; wherein said aryl, heteroaryl, heterocyclic and 05-10 cycloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo; hydroxyl; cyano; nitro; C1_3 alkoxy; C1_3 kyl; C1_3 haloalkoxy; 01-6 alkyl; 03-6 cycloalkyl; phenyl ally substituted with one to three substituents each independently selected from the group ting of: halo, hydroxyl, cyano, nitro, C1_3 alkoxy, C1_3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COORb, SOZRb, NHC(O)Rb, and NRbRb; 5-6 membered heteroaryl; 5-6 ed heterocyclic optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl; -CH2Ra; -ORa; —C(O)Ra; -NRaRb; -COORa; —SOzRa; NHC(O)Ra; and -SOZNRbRb; or R5b and R6 are joined together forming an optionally substituted 03-7 cycloalkyl group or an optionally substituted group of formula (a): (a), wherein n is 1, 2, or 3 and said 03-7 cycloalkyl and group of formula (a) are optionally tuted with one to three substituents each independently selected from the group consisting of: halo, yl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 ed heterocyclic, benzyloxy, COORb, sosz, NHC(O)Rb, and NRbRb; each R8 is independently optionally tuted phenyl, optionally substituted heteroaryl, or optionally substituted 4-7 ed heterocyclic, wherein said phenyl and heteroaryl are ally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, and 01-3 alkyl, wherein said 4-7 membered heterocyclic is optionally tuted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, 01-3 alkoxy, 01-3 kyl, 01-3 haloalkoxy, and 01-3 alkyl; and each Rb is ndently hydrogen or 01-6 alkyl.
In another embodiment of the present invention R1 is hydrogen, halo, or optionally substituted C1_4 alkyl. Suitably R1 is hydrogen, fluoro, chloro, or methyl. In r embodiment R1 is en, fluoro or chloro. Suitably R1 is hydrogen.
In another embodiment of the present invention R2 is hydrogen, halo or optionally substituted C1_4 alkyl. ly R2 is hydrogen, fluoro, , or methyl. In another embodiment R2 is hydrogen or fluoro. In another embodiment of the present invention R2 is hydrogen.
In another ment of the present invention R1 and R2 are both hydrogen.
In another embodiment of the present invention R38' is hydrogen, 01-6 alkyl, or phenyl. ly R38' is hydrogen, methyl, or phenyl. Suitably R38' is hydrogen or methyl. Suitably R38' is hydrogen.
In another embodiment of the present invention R3b is hydrogen or methyl.
Suitably R3b is hydrogen.
In another embodiment R38' and R3b are both hydrogen.
In another embodiment of the present invention R38' and R3b are joined together forming oxetanyl or tetrahydro-2H-pyranyl.
Another embodiment of the present invention is a compound according to formula (II).
NI \ o X / A HN N N In r embodiment of the present invention R48' is hydrogen, 01-6 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene, wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three tuents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_3 alkoxy, C1_3 haloalkyl, C1_3 koxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, —COORb, -SOZRb,- NHC(O)Rb, and- NRbRb .
In another embodiment of the present invention R48' is hydrogen, C1_4 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene. Suitably R48' is hydrogen, C1_4 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyridinyl, or ene-dibenzene. More suitably R48' is hydrogen, methyl, isopropyl, isobutyl, t- butyl, , 4-methoxyphenyl, 4-fluorophenyl, benzyl, or methylene-dibenzene. In another embodiment R48' is hydrogen, methyl, ethyl, isopropyl, phenyl, 4-fluorophenyl, 4- methoxyphenyl, yl, benzyl, or pyridinyl. Suitably R48' is isopropyl.
In another ment of the present invention R4b is hydrogen or methyl.
Suitably R4b is hydrogen.
In another embodiment R48' is isopropyl and R4b is methyl. In r embodiment R48' is isopropyl and R4b is hydrogen.
In another ment of the t invention R48' and R4b are joined together forming cyclopentyl.
Another embodiment of the t invention is a compound ing to formula (III).
NI \ o A / A HN N N R R (III) In another embodiment of the present invention R58' is hydrogen. In another embodiment R58' is deuterium.
In another embodiment of the t invention R5b is hydrogen, methyl, ethyl, or CF3. Suitably R5b is methyl.
In another embodiment of the present invention R6 is isopropyl, optionally substituted aryl, ally substituted pyrazolyl, optionally substituted pyridinyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or ally substituted 05-10 cycloalkyl. Suitably R6 is isopropyl, optionally substituted phenyl, optionally substituted naphthyl, pyrazolyl, pyridinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or 05-10 cycloalkyl, wherein said phenyl and naphthyl are each optionally substituted with one to three substituents each independently selected from the group consisting of: fluoro, chloro, bromo, hydroxy, cyano, methoxy, trifluoromethyl, methyl, t-butyl, , pyrrolyl, piperidinyl, ylpiperazinyl, morpholinyl, phenoxy, and 2.
In another embodiment of the present invention R6 is optionally substituted heteroaryl, optionally tuted heterocyclic or optionally substituted 05-10 cycloalkyl.
In another embodiment of the present invention R6 is methyl, C540 cycloalkyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted triazolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substitued 1,3,4-oxadiazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substitued isoxazolyl, thienyl, oxazolyl, quinolinyl, optionally substituted idazolyl, benzthiazolyl, benzoxazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, optionally substituted piperidinyl, optionally substituted piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, ally tuted tetrahydro-thiopyran1,1-dioxide, 1H-pyrrolo[2,3- b]pyridinyl, 2,3-dihydro—benzo[1,4]dioxinyl, 5,6,7,8—tetrahydro-[1,2,4]trazolo[4,3- a]pyrazinyl, 4,5,6,7-tetrahydro-benzothiazolyl, or indolizinyl, wherein said phenyl, pyridinyl, pyrimidinyl, zinyl, pyrazinyl, triazolyl, pyrazolyl, thiazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, isoxazolyl, benzimidazolyl, piperidinyl, piperazinyl, and tetrahydro-thiopyran1,1-dioxide are each optionally substituted with one or two substituents as defined in formula (I). Suitably R6 is phenyl optionally substituted with one or two substituents. Suitably R6 is optionally tuted oxadiazolyl or 1,2,4- optionally substituted oxadiazolyl. Suitably R6 is pyrimidinyl ally substituted with one substituent.
In another embodiment R6 is optionally substituted with one or two tuents each independently selected from the group consisting of: halo; hydroxy; nitro; C1_4 alkoxy; 01-3 kyl; 01-3 haloalkoxy; 01-6 alkyl; 03-6 cycloalkyl ally substituted with one substituent selected from the group consisting of: cyano, 01-3 alkyl, and 01-3 alkoxy; phenyl ally substituted with one or two substituents each independently ed from the group consisting of: fluoro, chloro, methyl, cyano, and methoxy; and 5- 6 membered heteroaryl (for example, imidazolyl, lyl, trazolyl, and pyridinyl) optionally substituted with one or two methyl .
In another embodiment R6 is substituted with one -CH2Ra, -C(O)Ra, —NHC(O)R3, -NHC(O)Rb, -C(O)NHRa, -C(O)NHRb, -0Ra, -NRaRb, -SOZNRbRb, —SOZR3, or -SOZRb group. Suitably R6 is substituted with one -CH2R3, -C(O)Ra, or —ORa group.
In another embodiment R6 is phenyl substituted with one fluoro or chloro group and one , -C(O)Ra, or -C(O)NHRa group wherein the -CH2Ra, -C(O)Ra, or —C(O)NHRa group is in the para position of the phenyl ring. Suitably R6 is phenyl substituted with one fluoro group and one -CH2Ra, -C(O)Ra, or -C(O)NHRa group wherein the -CH2Ra, -C(O)Ra, or -C(O)NHRa group is in the para position of the phenyl ring. In another embodiment R6 is phenyl substituted with one -CH2Ra, -C(O)Ra, or —C(O)NHRa group in the para position. In another ment R6 is phenyl substituted by -CH2Ra in the para position.
In another embodiment R8' is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of fluoro, chloro and bromo.
In another embodiment R8 is an optionally substituted 5-6 membered heteroaryl.
Suitably R8' is optionally substituted nyl or optionally tuted pyrimidinyl.
Suitably R8' is pyridinyl or pyrimidinyl optionally substituted with one oromethyl.
In r embodiment R8' is 05.7 cycloalkyl each of which is optionally substituted with one or two substituents each independently selected from the group consisting of fluoro, hydroxy, methyl, and C1_3 haloalkoxy.
In r ment R8 is optionally substituted heterocyclic. ly R8' is piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydro-thiopyran1,1-dioxide, 1,4-diazepanyl, 4,7-diaza-spiro[2.5]octanyl, 3,8—diaza-bicyclo[3.2.1]octanyl, 3,8—diaza- bicyclo[4.2.0]octanyl, octahydro-pyrrolo[1,2-a]pyrazinyl, octahydro-pyrido[1,2—a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, and 5,6,7,8—tetrahydro-imidazo[1,2—a]pyrazinyl each of which is optionally substituted with one to three substituents each independently selected 2012/055133 from the group consisting of: hydroxy, fluoro, amino, dimethylamino, C1_3 haloalkoxy, 01-3 alkyl, and 03-5 cycloalkyl. Suitably R8' is piperidinyl, piperazinyl, or morpholinyl each of which is optionally substitued with one to three tuents each independently selected from the group consisting of: hydroxy, fluoro, amino, dimethylamino, 01-3 haloalkoxy, 01-3 alkyl, and C3_5 cycloalkyl.
In another embodiment of the t invention R5b and R6 are joined together forming an optionally substituted 03-7 cycloalkyl group or an optionally substituted group of formula (a).
In another embodiment of the present invention each Rb is independently hydrogen or methyl.
In another ment R1 is hydrogen, R2 is fluoro and R33, R3b, R48' and R4b are each hydrogen.
Another embodiment of the present invention is a compound according to formula (IV).
NI \ o X / A HN N N R59” .
R 5a ' R3b R R R 3a (IV) Another embodiment of the present invention is a compound according to formula (V): NI \ o X / A HN N N R59“ R6 5a R4a E Rsb é4b 33 (V), wherein R48' is phenyl and R4b is hydrogen. ed compounds of the present invention e: (S)isopropy(2—(((S)—1-(4-(2-y|)phenyl)ethyl)amino)pyrimidinyl)oxazolidin-2—one; N-(4-((S)—1-(4-((S)—4-isopropyloxooxazolidinyl)pyrimidin-2— yIamino)ethy|)phenyl)cyclohexanecarboxamide; 2012/055133 (S)(2-(((S)—1-(3-f|uoro—4-((4-methy|piperazin y|)methyl)phenyl)ethyl)amino)pyrimidinyl)isopropy|oxazo|idin-2—one; (S)isopropyl(2—(((S)—1 -(4-((3,3,4-trimethylpiperazin y|)methyl)phenyl)ethyl)amino)pyrimidinyl)oxazolidinone; 2-fluoro—N-(4-hydroxymethylcyclohexyl)((S)—1-((4-((S)isopropyI-Z-oxooxazolidin- 3-yl)pyrimidin-2—y|)amino)ethy|)benzamide; (S)(2-((S)—1-(4-((4-amino—4-methylpiperidiny|)methyl)pheny|)ethylamino)pyrimidin y|)isopropy|oxazo|idin-2—one; (S)(2-((S)—1-(4-((4-(dimethylamino)piperidiny|)methy|)pheny|)ethylamino)pyrimidin- 4-y|)isopropy|oxazo|idin-2—one; (S)isopropyI(2-((S)(4-((4-methy|piperazin y|)methyl)phenyl)ethylamino)pyrimidinyl)oxazolidin-2—one; (S)isopropyImethyI(2-((S)(4-((4-methy|piperazin hyl)phenyl)ethylamino)pyrimidinyl)oxazolidin-2—one; isopropyl(2—((S)—1-(6-phenylpyridinyl)ethylamino)pyrimidinyl)oxazolidin-2— one; (S)(2—((S)—1-(4-benzoy|phenyl)ethylamino)pyrimidinyl)isopropy|oxazo|idin-2—one; (S)isopropyl(2—(((S)—1-(5-pheny|—1,3,4-thiadiazoI-Z-y|)ethy|) amino) pyrimidin y|)oxazo|idinone; (4S)—4-isopropy|—3-(2—(1-(5-pheny|pyrimidinyl)ethylamino)pyrimidinyl)oxazolidin-Z- one; 3-(5-fluoro—2-((1-(5-(4-f|uoro—3-methylphenyl)pyridin-2—y|)ethy|)amino)pyrimidin y|)oxazo|idinone; (S)isopropyl(2—(((S)—1-(1-(3-methoxypheny|)—1H-pyrazoIyl)ethy|)amino)pyrimidin- 4-y|)oxazo|idin-2—one; (S)(2-(((S)—1-(5-(4-f|uoropheny|)—1,3,4-oxadiazoIy|)ethy|)amino)pyrimidiny|) isopropyloxazolidinone; (S)(2-(((S)—1-(3-(4-ch|oropheny|)—1,2,4-0xadiazoIy|)ethy|)amino)pyrimidiny|) isopropyloxazolidinone; (S)isopropyl(2-(((S)—1-(3-(m-to|y|)—1,2,4-oxadiazoIy|)ethy|)amino)pyrimidin y|)oxazo|idinone; (S)(2-(((S)—1-(3-(4-f|uoropheny|)—1,2,4-oxadiazoIy|)ethy|)amino)pyrimidiny|) isopropyloxazolidinone; (S)(2-((S)—1-(5-(4-f|uoro—2-methy|phenyl)pyrimidiny|)ethy|amino)pyrimidiny|)—4- isopropyloxazolidinone; (S)|sopropyl{2—[(3-p-to|y|-[1,2,4]oxadiazoIylmethyl)-amino]—pyrimidiny|}- oxazolidin-Z-one; WO 46136 (S)isopropy|—3-(2-((S)—1-(4-(1-methy|—1H-pyrazoIyl)phenyl)ethylamino)pyrimidin y|)oxazo|idinone; (2—((S)—1-(2-f|uoro—4-isopropylpheny|)ethy|amino)pyrimidiny|) isopropyloxazolidinone; (S)(2-((S)—1-(4-isobutoxymethylpheny|)ethy|amino)pyrimidiny|)—4- isopropyloxazolidinone; (S)(2-(((S)—1-(4-isobutoxypheny|)ethy|)amino)pyrimidinyl)isopropy|oxazolidin one; (S)(5-f|uoro—2-(((S)—1-(4-isobutoxypheny|)ethyl)amino)pyrimidiny|) isopropyloxazolidinone; 2—fluoro—N-(transhydroxycyclohexyl)—4-((S)—1-(4-((S)isopropyl-2—oxooxazolidin y|)pyrimidinylamino)ethy|)benzamide; (S)(5-f|uoro—2-((S)—1-(3-f|uoro—4-(piperidinecarbony|)phenyl)ethylamino)pyrimidin y|)isopropy|oxazo|idin-2—one; N-Cyclohexylfluoro—4-((S)—1-(5-f|uoro((S)isopropyI-Z-oxooxazolidinyl)pyrimidin- 2—ylamino)ethy|)benzamide; N-cyclohexyl-2—fluoro—4-((S)—1-(4-((S)isopropyI-Z-oxooxazolidinyl)pyrimidin-2— y|amino)ethy|)benzamide; and (S)(5-f|uoro—2-((S)—1-(2-f|uoro—4-(trifluoromethyl)phenyl)ethylamino)pyrimidiny|) isopropyloxazolidinone.
Selected compounds of the present invention include: (S)(2—(((S)—1-(3-f|uoro—4-((3,3,4-trimethylpiperazin hyl)pheny|)ethy|)amino)pyrimidinyl)isopropy|oxazo|idin-2—one; (S)(2—(((S)—1-(4-((4,4-difluoropiperidiny|)methyl)phenyl)ethyl)amino)pyrimidiny|)— 4-isopropyloxazolidinone; (S)(5-f|uoro—2-(1-(4-phenoxyphenyl)ethylamino)pyrimidiny|)oxazolidin-Z-one; (S)(2—((S)—1-(4-(4-f|uorophenoxy)pheny|)ethylamino)pyrimidiny|) isopropyloxazolidinone; (S)(2—((S)—1-(4-(((28,6R)—2,6-dimethylmorpholino)methyl)phenyl)ethylamino)pyrimidin- 4-y|)isopropy|oxazolidinone; (S)(2—(((S)—1-(3-(4-ch|oropheny|)—1,2,4-oxadiazoIyl)ethyl)amino)pyrimidiny|) pyloxazolidinone; (S)(2—(((S)—1-(5-(4-ch|oropheny|)—1,2,4-oxadiazoIyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone; (S)(2—((S)—1-(5-(4-f|uoro—3-methylphenyl)pyridinyl)ethylamino)pyrimidiny|) isopropyloxazolidinone; (S)(2—((S)—1-(5-(4-fluorophenoxy)pyrimidinyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone; (S)(2—((S)—1-(5-(4-fluorophenoxy)pyrazinyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone; (S)isopropyl(2—((S)—1-(5-(3-(trifluoromethyl)phenyl)pyrimidin y|)ethylamino)pyrimidinyl)oxazolidinone; and (S)(2-((S)—1-(5-(4-fluoromethylphenyl)pyrimidinyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone.
Selected nds of the present invention include: (S)(2—(1-(3-(4-chlorophenyl)—1,2,4-oxadiazolyl)ethylamino)—5-fluoropyrimidinyl)— 4,4-dimethyloxazolidin-Z-one; (S)(6-chloro-2—(1-(3-(4-chlorophenyl)—1,2,4-oxadiazolyl)ethylamino)pyrimidin y|)oxazo|idinone; (2-((S)—1-(2-fluoro(1-methylcyclopropyl) phenyl) ethylamino) pyrimidinyl)—4- isopropyloxazolidinone; (S)(2-((S)—1-(2-fluoro (trifluoromethyl) phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone; 2—chloro-N-cyclopentyl((S)(4-((S)—4-isopropyloxooxazolidinyl)pyrimidin y|amino)ethy|)benzamide; (S)(2—((S)—1-(4-((3,3-difluoropiperidiny|)methyl)phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone; (S)(2-((S)—1-(4-(4,7-diazaspiro[2.5]octanylmethyl)phenyl)ethylamino)pyrimidinyl)— 4-isopropyloxazolidinone; (S)(2-((S)—1-(4-((4-acetylpiperaziny|)methyl)phenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone; (S)(2-(((S)—1-(4-isobutoxyphenyl)ethyl)amino)pyrimidinyl)isopropyloxazolidin one; (S)(5-fluoro(((S)—1-(4-isobutoxyphenyl)ethyl)amino)pyrimidinyl)—4- pyloxazolidinone; and 2-fluoro-N-(trans—4-hydroxycyclohexyl)—4-((S)—1-(4-((S)isopropyl-Z-oxooxazolidin y|)pyrimidinylamino)ethyl)benzamide.
Enumerated Embodiments ment 1. A compound of formula (I) Nl \ o A / A HN N N wherein: each R1 and R2 is independently hydrogen, deuterium, halo, hydroxyl, NH2, aryl, heteroaryl, or optionally substituted C1_4 alkyl, wherein said C1_4 alkyl is optionally substituted with one to three tuents each independently selected from the group consisting of: halo, hydroxyl, and NH2; R38' is hydrogen, deuterium, 01-6 alkyl, phenyl, or benzyl and R3b is hydrogen, deuterium, or 01-6 alkyl; or R38' and R3b are joined er forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered heterocyclic ring, wherein said cycloalkyl and heterocyclic rings are each optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and C1_3 alkyl; R48' is hydrogen, 01-6 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted aryl, or methylene-dibenzene, wherein said phenyl, benzyl, and heteroaryl rings are ally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_3 alkoxy, C1_3 kyl, C1_3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, y, COORb, sosz, NHC(O)Rb, and NRbRb and R4b is hydrogen, deuterium, or 01-3 alkyl; or R48 and R4b are joined together forming an optionally substituted 3-7 membered lkyl ring or an optionally substituted 4-7 membered heterocyclic ring, wherein said cycloalkyl and heterocyclic rings are optionally tuted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl, provided that only one of R33 and R3b and R48' and R4b are joined together g a ring; R58' is hydrogen or deuterium; R5b is hydrogen, ium, methyl, ethyl, CD3, CF3, CH2F, or CHF2 and R6 is optionally substituted 01-6 alkyl, ally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted 05-10 cycloalkyl, wherein said 01-6 alkyl is optionally substituted with one substituent ed from the group consisting of hydroxyl, C1_3 alkoxy and —ORa; wherein said aryl, heteroaryl, heterocyclic and 05-10 cycloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo; hydroxyl; cyano; nitro; C1_3 alkoxy; C1_3 haloalkyl; C1_3 haloalkoxy; 01-6 alkyl; 03-6 cycloalkyl; phenyl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_3 alkoxy, C1_3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COORb, SOZRb, NHC(O)Rb, and NRbRb; 5-6 membered heteroaryl; 5-6 membered heterocyclic ally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl; -CH2Ra; -ORa; -C(O)Ra; -NRaRb; -COORa; —SOzRa; NHC(O)Ra; and -SOZNRbRb; or R5b and R6 are joined together forming an optionally substituted 03-7 cycloalkyl group or an optionally substituted group of a (a): (a), n n is 1, 2, or 3 and said 03-7 cycloalkyl and group of formula (a) are optionally substituted with one to three tuents each independently ed from the group consisting of: halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 WO 46136 cycloalkyl, 5-6 ed heteroaryl, 5-6 membered heterocyclic, oxy, COORb, sosz, NHC(O)Rb, and NRbRb; each R8' is independently optionally substituted , optionally substituted heteroaryl, or optionally substituted 4-7 membered heterocyclic, wherein said phenyl and heteroaryl are optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, and 01-3 alkyl, wherein said 4-7 membered heterocyclic is optionally substituted with one to three substituents each independently ed from the group consisting of halo, hydroxyl, oxo, C1_3 alkoxy, C1_3 haloalkyl, C1_3 haloalkoxy, and 01-3 alkyl; and each Rb is independently hydrogen or 01-6 alkyl; or a pharmaceutically acceptabble salt thereof.
Embodiment 2. The compound according to embodiment 1 n R2 is hydrogen; or a pharmaceutically acceptable salt thereof.
Embodiment 3. The compound according to embodiment 2 wherein R1 is hydrogen, halo, or optionally tuted C1_4 alkyl; or a pharmaceutically acceptable salt thereof.
Embodiment 4. The compound ing to embodiment 3 wherein R1 is hydrogen, fluoro, chloro, or methyl; or a pharmaceutically acceptable salt thereof.
Embodiment 5. The compound according to embodiment 4 wherein R38' is en, 01-6 alkyl, phenyl, or benzyl and R3b is hydrogen or 01-6 alkyl; or a pharmaceutically acceptable salt f.
Embodiment 6. The compound according to embodiment 5 wherein R3b is hydrogen or ; or a pharmaceutically acceptable salt thereof.
Embodiment 7. The compound according to embodiment 6 wherein R38' is hydrogen, methyl, or phenyl; or a pharmaceutically acceptable salt thereof.
Embodiment 8. The compound according to embodiment 7 wherein R48' is hydrogen, C1-6 alkyl, optionally substituted , optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene, wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_3 alkoxy, C1_3 haloalkyl, C1_3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, COORb, SOZRb, NHC(O)Rb, and NRbRb and R4b is hydrogen or C1_3 alkyl; or a pharmaceutically acceptable salt thereof.
Embodiment 9. The compound according to embodiment 8 wherein R4b is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
Embodiment 10. The compound according to embodiment 9 wherein R48' is hydrogen, C1_4 alkyl, optionally substituted , optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene; or a pharmaceutically acceptable salt thereof.
Embodiment 11. The compound according to embodiment 10 wherein R48' is hydrogen, , isopropyl, yl, t-butyl, phenyl, 4-methoxyphenyl, 4-fluorophenyl, benzyl, or methylene-dibenzene; or a pharmaceutically acceptable salt thereof.
Embodiment 12. The compound according to ment 11 wherein R58' is H; or a pharmaceutically acceptable salt thereof.
Embodiment 13. The compound ing to embodiment 12 wherein R5b is hydrogen, , ethyl, or CF3.
Embodiment 14. The compound ing to embodiment 13 wherein R6 is pyl, optionally substituted aryl, optionally substituted pyrazolyl, optionally substituted pyridinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or optionally substituted 05-10 lkyl; or a ceutically acceptable salt thereof. 2012/055133 Embodiment 15. A pharmaceutical composition comprising a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Embodiment 16. A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to ment 1, or a pharmaceutically acceptable salt thereof, to subject in need of thereof.
Embodiment 17. A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to embodiment 1, or a pharmaceutically able salt f, and another therapeutic agent to subject in need of thereof.
General tic Procedures The compounds of the present invention may be made by a variety of methods, including standard chemistry. le tic routes are depicted in the Schemes given below.
The compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the ing synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in ance with general principles or try. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of formula (I).
Those skilled in the art will recognize if a stereocenter exists in the compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or reomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any ient intermediate. Resolution of the final product, an intermediate, or a starting al may be effected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, s. H. Wilen, and L. N.
Mander (Wiley-lnterscience, 1994).
The compounds described herein may be made from commercially available starting materials or synthesized using known c, nic, and/or enzymatic processes. was;NH Mm N H H E H' 0 0H 1L 2’_. ’2 R4a R4b R4H WH R4b O R4b O 1 2 3 Non-commercial aminoacids can be prepared following the procedures of Scheme 1. Conversion of ketone 1 to the corresponding imidazolidine-2,4-dione 2 followed by hydrolysis provides aminoacid 3.
Scheme 2.
WhenR33——R3b (RCO)20 H2“ OH SOCI2,MeOH H2N OMe )L HZC|2 NH OMe R4a —> R4a —> R4a R4123 0 R4; 0 R = tBu or CF3 R4b50 (RCO)ZO When R335: R3b R3aMgBr 33" CHZC'Z THF or EtZO o o R)LNH OH R>LNH OH R4aH 5 8 R43 3a R4b O R4b R3a e-HCI LiOH 0r TFA TBTU,iPr2NEt, DMF IPrOH, H20 CHzClz )L \ H N NH N/OMe 2 OH R 43H 7 9 48H R R3a l 1)R3aMgBr,THF 2 ) R3bMgB r, THF 0 triphosgene R)LNH OH LiOg Cong:CI HZN OH ngch2 R4aH 3b“) r H,H R4aH 3b Et2003,NaOMe,MeOH R4bR3 R4bR3B or 11 N,N'-carbony|diimidazole, HNJko R4bR3B3b When aminoalcohol, precursor of oxazolidinone, is not commercially available, it can be prepared from aminoacid 3 following the procedures of Scheme 2. When R3“1 = Rsb, protected aminoester 5 is treated with an appropriate Grignard reagent to give protected aminoalcohol 6 which goes through basic or acidic deprotection step. When R3“1 at Rsb, protected aminoacid 8 is converted into Weinreb amide 9 which is treated with different rd reagents sequentially to provide protected aminoalcohol 10. Either basic or acidic deprotection of 10 gives 11. Insertion of CO unit into 7 or 11 to provide idinone 12 is accomplished with several reagents, including (but not limited to) triphosgene, EtZCO3 or N-N’-darbonyldiimidazole, as shown in Scheme 2.
Scheme 3.
O ”Hi R 1 R 1 JL NH R2 2 + 15 R2 HN O XAN/ 13 N \ 0 R551 R5b DMSO N \ heatin O 1 X2 X1)\N/ NAl R ’ g R43H53b 6 A /I R4bR3 NaH, DMF R43HO with or t iPerEt O 3b R5b+ R5b R43H 3b 12 14 R4bR3a R stOH, nBuOH, heating R6 16 R4bR3a R Oxazolidinone 12 is coupled with dihalogen-pyrimidine 13 in the presence of NaH and the resulting 14 is d with primary amine 15 under l different reaction conditions as shown in Scheme 3 to provide 16.
Scheme 4.
R1 R1 N \ R2 R2 H2N OH J'x 13 x1 N/ x2 WH3b )NL \ triphosgene- )NL \ —> X1 N/ R4DR3§ NH x1 N/ NA NaH, DMF R43HOH Sgwgtdgfc WHO 11 R4bR3a R3b 14 R4bR3a R3b Alternately intermediate 14 can be prepared by coupling the amino alcohol 11 and dihalogen-pyrimidine 13 in the presence of a base such as diisopropylethyl amine resulting in intermediate 17 which can be treated with triphosgene in the presence of a base such as 2,6-lutidine resulting in intermediate 14.
Methods of Use The nds of the present invention are inhibitors of a mutant IDH protein having a neomorphic activity and are therefore useful in the treatment of diseases or disorders associated with such proteins including, but not limited to, cell proliferation disorders, such as .
Examples of a mutant IDH protein having a phic activity are mutant IDH1 and mutant IDH2. A phic ty associated with mutant IDH1 and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HG neomorphic activity), specifically R HG (RHG neomorphic activity). Mutations in IDH1 associated with 2-HG neomorphic activity, specifically RHG neomorphic activity, include mutations at residues 97, 100, and 132, e.g. G97D, R1OOQ, R132H, R1320, R1328, R132G, R132L, and R132V.
Mutations in IDH2 associated with 2-HG neoactivity, specifically RHG neomorphic activity, include mutations at residues 140 and 172, e.g. R14OQ, R140G, R172K, R172M, R1728, R172G, and R172W.
Cell-proliferation disorders associated with a mutant IDH protein having a neomorphic ty include, but are not limited to, cancer. Examples of such cancers include Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, ood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder ; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem , Childhood; Brain Tumor, llar ytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, ood; Brain Tumor, Medulloblastoma, ood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial as/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; oma, Islet Cell; Carcinoma of Unknown Primaiy; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical ; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; moma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct ; Eye Cancer, lntraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, ood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood ry); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual y , ood; cular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); 's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, c Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung , all Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic ia, Chronic; Lymphoma, AlDS- Related; Lymphoma, Central Nervous System (Primary); ma, Cutaneous ; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy;Lymphoma, Non-Hodgkin' s, Adult; Lymphoma, Non- n's, Childhood; Lymphoma, Non- Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; ant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, lntraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple ine Neoplasia Syndrome, Childhood; le Myeloma/Plasma Cell Neoplasm; s Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid ia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's ma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal ; steosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian lial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; atic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive ctodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, ood; Salivary Gland Cancer; Salivary Gland Cancer, ood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft , Adult; Sarcoma, Soft Tissue, ood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung ; Small Intestine ; Soft Tissue Sarcoma, Adult; Soft Tissue a, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; a, ant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine a; Vaginal Cancer; Visual Pathway and Hypothalamic G|ioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor.
In another embodiment the cancer associated with a mutant IDH protein having a neomorphic acitvity is brain cancer, such as astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic astrocytoma, anaplastic ytoma, astrocytoma, giant cell g|iob|astoma, g|iob|astoma, secondary g|iob|astoma, primary adult g|iob|astoma, and primary pediatric g|iob|astoma); o|igodendroglial tumor (e.g., o|igodendrog|ioma, and anaplastic o|igodendrog|ioma); o|igoastrocytic tumor (e.g., o|igoastrocytoma, and anaplastic strocytoma); ependymoma (e.g., myxopapillary ependymoma, and anaplastic moma); medulloblastoma; primitive neuroectodermal tumor, noma, meningioma, meatypical meningioma, anaplastic meningioma; and pituitary adenoma.
In another embodiment, the brain cancer is g|ioma, g|iob|astoma multiforme, paraganglioma, or suprantentorial primordial ctodermal tumors (sPNET).
In another embodiment the cancer ated with a mutant IDH protein having a neomorphic acitvity is leukemia, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), MDS.MPN ing chronic myelomonocytic leukemia, post MDS AML, post MPN AML, post MDS/MPN AML, del(5q)—associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, mmunoblastic lymphoma and acute blastic leukemia.
In another ment the cancer associated with a mutant IDH protein having a neomorphic activity is skin cancer, including melanoma.
In another embodiment the cancer associated with a mutant IDH protein having a phic activity is prostate cancer, thyroid cancer, colon cancer, or lung cancer.
In another embodiment the cancer associated with a mutant IDH protein having a neomorphic activity is sarcoma, including central chondrosarcoma, l and periosteal chondroma, and fibrosarcoma.
In another embodiment the cancer associated with a mutant IDH n having a neomorphic activity is cho|angiocarcinoma.
Another disease or disorder associated with a mutant IDH protein having RHG neomorphic activity is Dhydroxyglutaric aciduria.
Another disease or disorder associated with a mutant IDH protein having RHG neomorphic activity is Diller e and Mafucci syndrome.
As used herein the term rphic activity” refers to a gain of novel activity of a protein that the wild-type protein does not have or does not exhibit to a icant degree. For example, a neomorphic ty associated with a mutant form of IDH1 and IDH2 is the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2—HG, specifically R-2—HG). The wild type form of IDH1 and IDH2 does not have the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2—HG, specifically RHG) or if it does have this ability, it does not produce significant (i.e. harmful or disease causing) amounts of 2—HG.
As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other ments, the subject is a human.
As used herein, the term “therapeutically effective amount” in reference to a compound of the invention means an amount of the compound sufficient to treat the subject’s disease or condition, but low enough to avoid serious sides effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A therapeutically ive amount of a compound will vary with the ular compound chosen (e.g. er the potency, efficacy, and half-life of the compound); the route of administration ; the condition being treated; the severity of the condition being d; the age, size, weight, and al ion of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of the concurrent therapy; the desired eutic effect; and like s and can be routinely determined by the skilled artisan.
As used herein, the term “treat”, “treating" or "treatment" of any disease or er refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical ter including those which may not be discernible by the patient. In yet another embodiment, “treat”, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a al ter), or both. In yet another embodiment, ”, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
The compounds of the present invention may be administered by any suitable route including oral and parenteral administration. Parenteral administration is typically by injection or infusion and includes intravenous, intramuscular, and subcontaneous injection or infusion.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For e, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half life which can be determined by the d n. In addition, le dosing regimens, including the duration such regimens are stered, for a compound of the invention depend on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the subject being treated, the l history of the t being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled ns that suitable dosing regimens may require adjustment given an individual t’s response to the dosing regimen or over time as the individual subject needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration, to a human weighing approximately 70kg would range from about 5mg to about 500mg of a compound of formula (I).
One embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having a neomorphic activity comprising stration of a therapeutically effective amount of a compound of formula (I) to a subject in need of treatment thereof. In one embodiment, the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell eration disorder. In another ment, the cell proliferation er is cancer. In another embodiment, the cancer is a cancer associated with mutant IDH1 having 2—HG neomorphic activity or mutant IDH2 having 2—HG neomorphic activity. In another ment the neomorphic activity is R-2—HG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or RHG neomorphic activity having a mutation at residues 97, 100, or 132, such as 697D, R1OOQ, R132H, R132C, R1328, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or RHG neomorphic ty having a on at residues 140 or 172, e.g. R14OQ, R140G, R172K, R172M, R1728, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is g|ioma, g|iob|astoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute mye|oid leukemia, mye|odysp|astic syndrome, c mye|ogenous leukemia, melanoma, prostate, thyroid, colon, lung, l chondrosarcoma, central and periosteal chondroma , fibrosarcoma, and cholangiocarcinoma. r embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having RHG neomorphic activity comprising administration of a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof wherein the disease or er is D- 2-hydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
Another embodiment of the present invention provides for the use of a compound of formula (I) in y. In a further embodiment the therapy is a disease or disorder associated with a mutant form of IDH having a neomorphic ty. In another embodiment the therapy is a cell proliferation disorder associated with a mutant form of IDH having a neomorphic activity. In another embodiment the therapy is cancer. In another embodiment the therapy is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the phic activity is RHG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or RHG neomorphic activity having a mutation at residues 97, 100, or 132, such as 697D, R1OOQ, R132H, R132C, R1328, R132G, R132L, and R132V. In another embodiment the cancer is associated with mutant IDH2 having 2-HG or RHG neomorphic activity having a mutation at residue at residues R140 or 172, e.g. R14OQ, R14OG, R172K, R172M, R1728, R172G, and R172W. In another ment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid , colon cancer, lung cancer or sarcoma. In another embodiment the cancer is g|ioma, astoma multiforme, paraganglioma, tentorial primordial neuroectodermal tumors, acute mye|oid leukemia, mye|odysp|astic syndrome, c mye|ogenous leukemia, melanoma, te, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma. r embodiment of the present invention provides for the use of a compound of formula (I) in therapy wherein the therapy is Dhydroxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
Another embodiment of the present invention provides for the use of a compound ing to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having a phic activity. In one embodiment the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder. In another embodiment, the cell proliferation disorder is cancer. In another embodiment the cancer is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic ty or mutant IDH2 having 2-HG neomorphic activity. In another embodiment the neomorphic activity is RHG neomorphic activity. In another embodiment the cancer is associated with mutant IDH1 having 2-HG or RHG neomorphic activity having a mutation at residues 97, 100, or 132, such as 697D, R1OOQ, R132H, R132C, R1328, R132G, R132L, and R132V. In r embodiment the cancer is associated with mutant IDH2 having 2-HG or RHG neomorphic activity having a mutation at residue at residues 140 or 172, e.g. R14OQ, R14OG, R172K, R172M, R1728, R172G, and R172W. In another embodiment the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is glioma, astoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, l chondrosarcoma, central and periosteal chondroma , fibrosarcoma, and cholangiocarcinoma.
Another embodiment of the present invention provides for the use of a compound according to a (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having RHG neomorphic activity wherein the e or disorder is droxyglutaric aciduria, Ollier Disease, or Mafucci Syndrome.
Compositions In another aspect, the t invention provides a pharmaceutical ition comprising a nd of formula (I) and a ceutically acceptable r or excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a therapeutically effective amount of a compound of the invention can be extracted and then given to a subject, such as with powders or .
Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a therapeutically effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from about 5mg to 500mg of a compound of formula (I).
As used herein the term “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable material, composition or vehicle that, for example, are involved in giving form or consistency to the pharmaceutical ition. Each excipient must be compatible with the other ients of the pharmaceutical composition when gled such that ctions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically able are avoided. In addition, each excipient must, of course, be of sufficiently high purity to render it pharmaceutically acceptable.
The compound of the invention and the pharmaceutically acceptable carrier or ent(s) will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, es, caplets, pills, s, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution. le pharmaceutically acceptable excipients will vary ing upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the ition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the nd or compounds of the ion, once administered to the subject, from one organ or portion of the body to another organ or another portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the ing types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, g , ts, co-solvents, suspending agents, emulsifiers, sweeteners, ing agents, flavor g agents, coloring agents, aking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
Skilled ns possess the knowledge and skill in the art to enable them to select suitable pharmaceutically able carriers and excipients in appropriate s for the use in the invention. In addition, there are a number of resources available to the skilled artisan, which describe pharmaceutically acceptable carriers and excipients and may be useful in ing suitable pharmaceutically acceptable carriers and excipients. Examples include Remington’s Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American ceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack hing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler. Suitable ts and fillers include lactose, sucrose, dextrose, ol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized ), cellulose and its tives, (e.g. microcrystalline ose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder.
Suitable binders include starch (e.g. corn starch, potato starch, and pre—gelatinized starch) gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may r comprise a disintegrant. Suitable disintegrants include vidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as, for example, by coating or ing particulate material in polymers, wax, or the like.
The compounds of the ion may also be coupled with soluble polymers as targetable drug carriers. Such polymers can e polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention may be coupled to a 2012/055133 class of biodegradable rs useful in achieving controlled release of a drug, for example polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanacrylates and linked or amphipathic block copolymers of hydrogels.
In another aspect, the invention is directed to a liquid oral dosage form. Oral liquids such as solution, syrups and elixirs can be ed in dosage unit form so that a given quantity contains a predetermined amount of a compound of the ion. Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution; while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound of the invention in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and y ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or other natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.
In another aspect, the invention is directed to parenteral administration.
Pharmaceutical itions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain xidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in ose or multi-dose ners, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for ions, immediately prior to use. Extemporaneous ion solutions and suspensions may be prepared from sterile powders, granules and tablets.
Combinations The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic s). The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same ceutical composition as the other agent(s).
In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one ment, the therapy is the treatment of a disease or disorder ated with a mutant form of lDH. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other eutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
In one embodiment, the ion provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a nd of formula (I).
In one embodiment, the kit ses means for separately retaining said compositions, such as a container, divided bottle, or divided foil . An example of such a kit is a blister pack, as typically used for the ing of tablets, capsules and the like.
The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the ion, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic agent may be brought er into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the ion and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient lves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
Accordingly, the invention provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the medicament is ed for administration with another eutic agent. The invention also provides the use of another therapeutic agent for treating a disease or er ated with a mutant form of IDH, wherein the medicament is administered with a compound of formula (I).
The invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the nd of formula (I) is prepared for administration with another therapeutic agent.
The invention also es another therapeutic agent for use in a method of ng a disease or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The invention also es a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is stered with another eutic agent. The invention also provides another therapeutic agent for use in a method of treating a e or disorder associated with a mutant form of IDH, wherein the other therapeutic agent is administered with a compound of formula (I).
The invention also provides the use of a compound of a (I) for treating a disease or disorder associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or er associated with a mutant form of IDH, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).
In one embodiment, the other therapeutic agent is selected from: vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxic agents.
Examples of vascular endothelial growth factor (VEGF) receptor tors include, but are not limited to, bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl[[3-[(E)—2-pyridinylethenyl]-1H-indazol yl]sulfanyl]benzamide, also known as AGO13736, and described in PCT Publication No.
WO 01/002369), Brivanib Alaninate ((S)—((R)—1-(4-(4-Fluoromethyl-1H-indolyloxy)- ylpyrrolo[2,1-fl[1,2,4]triazinyloxy)propanyl)2-aminopropanoate, also known as BMS—582664), motesanib (N~(2,3—dihydrofi,3~dimethyl—1 oE—8~yl)—2~{(4— pyridimy!methyl)amin03—3wpyridinecarboxamide, and described in PCT Publication No, WC) 02(0563470}, otide (also known as 230, and described in EST Publication No. WO 03010192). and sorafenib (sold under the tradename Nexavar®).
Examples of topoisomerase II tors, e but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), and teniposide (also known as VM-26, sold under the tradename Vumon®).
Examples of alkylating agents, e but are not limited to, temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename en®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames ex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), Iomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), hosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTlC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), ifosfamide (sold under the tradename lfex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and roethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the ame Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, and sold under the tradename ex®.
Examples of anti-tumor antibiotics include, but are not d to, doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename ome®), mitoxantrone (also known as DHAD, sold under the tradename rone®), epirubicin (sold under the tradename EllenceT'V'), idarubicin (sold under the tradenames in®, ldamycin PFS®), and mitomycin C (sold under the tradename Mutamycin®). es of anti-metabolites include, but are not limited to, claribine (2- chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), guanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar—U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytT'V'), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames ®, DroxiaT'VI and MylocelT'V'), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename tinT'V'), methotrexate (also known as amethopterin, rexate sodim (MTX), sold under the ames Rheumatrex® and TrexallT'V'), and pentostatin (sold under the tradename Nipent®).
Examples of ids include, but are not limited to, alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), lsotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, ®, Decutan®, lsotane®, lzotech®, Oratane®, lsotret®, and Sotret®), and bexarotene (sold under the tradename Targretin®). es of other xic agents include, but are not limited to, arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, and EnNinia L-asparaginase, sold under the tradenames ® and Kidrolase®).
Intermediates and Examples The following examples are intended to be illustrative only and not limiting in any way. Unless ise noted, the following Intermediates and Examples were ed vial silica gel column chromatograph using RediSep® Rf columns from Teledyne lsco, lnc. Abbreviations used are those conventional in the art or the following: ACN acetonitrial BSA bovine serum albumin C Celsius CDI 1,1’-carbonyldiimidazole d doublet dd doublet of doublets DAST diethylaminosulfurtrifluoride DEAD diethyl azodicarboxylate DIPEA NN-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DTT threitol EtOAc ethyl acetate EtOH ethanol g gram h hour(s)HATU 2—(1Hazabenzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate HEPES 4-(2-hydroxyethyl)—1-piperazineethylanesulfonic acid HPLC high pressure liquid chromatography Hunig’s Base NN-diisopropylethylamine kg kilogram L liter LC liquid chromatographyLCMS liquid chromatography and mass spectrometry MeOH ol MS mass spectrometry m multiplet min minutes mL milliliter(s) uM micromolar m/z mass to charge ratio nm nanometer nM nanomolar N normal NADPH nicotinamide adenine dinucleotide phosphate NMP N-methylpyrrolidone NMR nuclear magnetic resonance PdC|2(dppf).CHZC|2 1,1’-bis(diphenylphosphino)ferrocene-palladium(l|)dichloride romethane x stOH enesu|fonic acid rac racemic Rt retention time s singlet sat. saturated t triplet TBTU O-(Benzotriazolyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TCEP tris(2-carboxyethyl)phosphine TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS—CN trimethylsilyl cyanide Instrumentation LCMS: LCMS data (also reported herein as simply M8) were recorded using a Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C18 1.8- , 2.1 x 50 mm; gradient: 5-95 % acetonitrile in water with 0.05 % TFA over a 1.8 min period; flow rate 1.2 mL/min; molecular weight range 200-1500; cone e 20 V; column temperature 50 °C). All masses reported are those of the protonated parent ions unless recorded othenNise.
High Resolution Mass Spectrometry (HRMS): HRMS Method A: ESl-MS data were recorded using a Synapt G2 HDMS (TOF mass spectrometer, Waters) with electrospray ionization source. The resolution of the MS system was approximately 15000. e Enkephalin was used as lock mass (internal rds) infused from lockspary probe. The compound was infused into the mass spectrometer by UPLC (Acquity, Waters) from sample probe. The separation was performed on Acquity UPLC BEH C18 1x50 mm column at 0.2 mL/min flow rate with the gradient from 5% to 95% in 3 min. t A was Water with 0.1% Formic Acid and solvent B was Acetonitrile with 0.1% Formic Acid. The mass accuracy of the system has been found to be <5 ppm with lock mass.
HRMS Method B: LC-MS/ESl-MS data were recorded on an Acquity G2 Xevo QTof - Rs(FWHM) > 20000 Accuracy < 5 ppm. The separation was performed on Acquity CSH 1.7um mm - 50°C column Eluent A: Water + 3.75 mM ammonium acetate. Eluent B: Acetonitrile. Gradient: from 2 to 98% B in 4.4 min - flow 1.0 mL/min.
HRMS methods A and B are referred to throughout as HRMS(A) or HRMS(B), respectively.
Intermediates Intermediate A: (R)—4-isobutyloxazolidinone HN 0 To a cooled (4 °C) solution of (R)—2-amino—4-methylpentano| (2.98 g, 25.4 mmol) and triethylamine (7.6 mL, 54 mmol, 2.1 equiv) in CH2C|2 (80 mL) was added dropwise a solution of triphosgene (2.52g, 8.49 mmol, 0.334 equiv) in 10 ml of CH2C|2 over 30 min.
The reaction mixture was stirred at 4 °C for 15 min, warmed up to room temperature and stirred for an additional 1 h. The mixture was treated with saturated NH4C| (25 mL), followed by CH2C|2 (50 mL) and the resulting e was d for 20 min. The layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with CH2C|2 (50 mL). The combined organic layers were dried over , filtered and concentrated to give (R)isobutyloxazolidinone (3.22 g) in 88% yield. The crude product was used for the next reaction without cation. 1H NMR (400 MHz, CD30D) 8 4.53 — 4.47 (m, 1 H), 4.00 — 3.92 (m, 2 H), 1.67 (ddq, J = 13, 8.0, 6.5 Hz, 1 H), 1.56 — 1.48 (m, 1 H), 1.40 — 1.32 (m, 1 H), 0.95 (d, J = 6.1 Hz, 3 H), 0.93 (d, J = 6.1 Hz, 3 H).
The Intermediates in Table 1 were prepared by a method similar to the one described for the preparation of Intermediate A.
Table 1.
Intermediate B Intermediate C Intermediate D Intermediate K Intermediate L — Table 2. Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed in Table 1.
Intermediate: Name 1H NMR 400 MHz 5 ppm LCMS B: (S)isobutyloxazolidin (CDCI3) 6.59 (br s, 1 H), 4.53 — 4.48 no UV signal one (m, 1 H), 4.01 — 3.92 (m, 2 H), 1.71 — 1.54 (m, 2 H), 1.42 — 1.35 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.93 (d, J = C: (S)—4-tert-butyloxazolidin (CD30D) 4.37 (t, J = 9.1 Hz, 1 H), 4.23 no UV signal one (dd, J = 9.1, 5.6 Hz, 1 H), 3.61 (dd, J = 9.1, 5.6 Hz, 1 H , 0.90 s, 9 H D: (48,5R)methy| (CD30D) 5 7.42 — 7.32 (m, 3 H), 7.27 _ no uv signal phenyloxazolidinone 7.24 (m, 2 H), 5.05 (dq, J = 8.0, 6.4 Hz, 1 H), 4.98 (d, J = 8.0 Hz, 1 H), 0.89 d, J = 6.5 Hz, 3 H E: (S)—4-(pyridin MS m/z yl)oxazolidinone 165.1 (M + F: (S)—4-(pyridin (CDCI3) 8.62 (dt, J = 5.4, 1.1 Hz, 1 H), ) yl)oxazolidinone 7.80 (td, J = 7.8, 1.5 Hz, 1 H), 7.45 (d, m/z 165.0663 J = 7.5 Hz, 1 H), 7.33 — 7.28 (m, 1 H), (M + H)+ 6.40 (br s, 1 H), 5.12 (dd, J = 8.8, 5.8 Hz, 1 H), 4.86 (t, J = 9.0 Hz, 1 H), 4.43 dd, J = 8.5, 5.5 Hz, 1 H G: (S)—4-(pyridin (CDCI3) 8.67 — 8.66 (m, 2 H), 7.36 — HRMS(B) yl)oxazolidinone 7.34 (m, 2 H), 6.50 (br s, 1 H), 5.04 — m/z 165.0664 .00 (m, 1 H), 4.80 (t, J = 8.8 Hz, 1 H), (M + H)+ 4.16 dd, J = 8.5, 6.5 Hz, 1 H H: (S)—4-methyl (CDCI3) 7.45 — 7.33 (m, 5 H), 6.10 (br ) s, 1 H), 4.39 (q, J = 8.4 HZ, 2 H), 1.79 m/Z 178.0871 s, 3 H M + H + 1.40 s, 6 H J: (S)—4-methy|—4- ) 7.33 — 7.19 (m, 5 H), 6.86 (br MS m/z phenyloxazolidinone s, 1 H), 4.32 — 4.27 (m, 2 H), 1.67 (s, 3 177.9 (M + K: (R)—4-(4-f|uoropheny|)—4- (CDCI3) 5 7.41 — 7.36 (m, 2 H), 7.14 — MS m/z methyloxazolidinone 7.08 (m, 2 H), 6.06 (br s, 1 H), 4.39 (d, 195.9 (M + J = 8.3 Hz, 1 H), 4.33 (d, J = 8.3 Hz,1 H)+ L: 3-oxaazaspiro[4.4]nonan- (CDCI3) 6 5.62 (br s, 1 H), 4.25 (s, 2 no UV signal 2-one H, 1.90 — 1.65 m, 8 H Intermediate M: 4-phenyl-1,8-dioxaazaspiro[4.5]decanone Step 1: Preparation of 4-(amino(phenyl)methyl)tetrahydro-2H-pyrano| To dihydro—2H-pyran-4(3H)—one (1001 mg, 10 mmol) and triethylamine (0.279 mL, 2.00 mmol) was slowly added TMS—CN (1190 mg, 12.00 mmol) [Caution: exothermic reaction]. After stirring for 1hour, the mixture was concentrated under reduced pressure.
The residue, dissolved in diethyl ether (10 mL), was added dropwise to phenylmagnesium bromide (3M solution in diethyl ether, 4.33 mL, 13.00 mmol).
Additional ~5 mL of diethyl ether was added and the suspension was stirred for ~4 hour.
To the reaction mixture was added very slowly MeOH (3.0 mL), followed by the careful and slow additions of NaBH4 (454 mg, 12.00 mmol) and MeOH (12 mL) in portions (gas development observed). The on mixture was stirred overnight and water (~6 mL) was added carefully, followed by 10% aqueous HCI solution (~20 mL). The mixture was vigrously stirred for 4 hour and diethyl ether was added. The separated organic layer was extracted with 10% aqueous HCI solution (1x ~20 mL). The ed aqueous layers were washed with diethylether (2x). The acidic layers were made basic by the addition of 6N aqueous NaOH solution. The milky white e was ted with DCM (1x), ethyl acetate/THF (1:1; 1x) and ethyl e (2x). The organic layers (DCM and ethyl acetate solutions independently) were washed with saturated aqueous NaHCO3 solution, dried over Na2804, filtered off and concentrated under reduced pressure providing crude 4-(amino(phenyl)methyl)tetrahydro-2H-pyranol, which was directly used in the next reaction without r purification. ish liquid. Yield: 451 mg. LCMS m/z 208.2 (M + H)+, Rt 0.29 min.
Step 2: Preparation of 4-phenyl-1,8-dioxaazaspiro[4.5]decanone To a e of CDI (388 mg, 2.394 mmol) in THF (1.5 mL) was added slowly a solution of 4-(amino(phenyl)methyl)tetrahydro-2H-pyranol (451 mg, 2.176 mmol) in THF (3 mL). The mixture was stirred under argon for ~5 hours. The e was d with saturated aqueous NaHCO3 solution and DCM. The separated aqueous layer was extracted with DCM (2x) and the combined organic layers were washed with 0.5N aqueous HCI solution and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column tography [Si02, 12 g, 0 - 100% heptane/ethyl acetate] providing yl-1,8-dioxaazaspiro[4.5]decan one as a white solid. Yield: 330 mg. LCMS m/z 234.1 (M + H)+; Rt 0.52 min.
Intermediate N: (S)(biphenyly|)oxazolidinone Step 1: Preparation of vinylbiphenyl To a suspension of triphenylphosphonium bromide (5.10 g, 14.27 mmol) in THF (26 mL) was slowly added potassium tert-butoxide (1M solution in THF, 14.27 mL) over ~20 min at 0 °C. The reaction mixture was allowed to warm up to room temperature and stirred for 10 min. The mixture was cooled to 0°C and a solution of 4- biphenylcarbaldehyde (2.0 g, 10.98 mmol) in THF (9 mL) was added over 20 min. The reaction mixture was d to warm up to room temperature and stirred for ~19 hour.
The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved/suspended in DCM and filtered through a silica pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [Si02, 80 g, heptane] to provide vinylbiphenyl (1.845 g) as a white solid. LCMS Rt 0.79 min.
Step 2: Preparation of (S)-tert-butyl 1-(bipheny|y|)hydroxyethylcarbamate To a solution of tert-butyl carbamate (2.82 g, 24.08 mmol) in 1-propanol (30 mL) was added aqueous NaOH solution (0.38M, 61.5 mL, 23.36 mmol). The mixture was stirred for 5 min and chloro-5,5-dimethylimidazolidine—2,4-dione (2.351 g, 11.93 mmol) was added. The mixture was stirred stirred for 10 min and (DHQ)2PHAL (0.303 g, 0.388 mmol), dissolved in 1-propanol (30 mL), was added followed by a solution of vinylbiphenyl (1.4 g, 7.77 mmol) in 1-propanol (60 mL). A suspension of potassium osmate dihydrate (0.114 g, 0.311 mmol) in aqueous NaOH on, (0.38M, 0.613 mL, 0.233 mmol) was added and the mixture was stirred for ~ 16 hours. The on mixture was diluted with water (200 mL) and ted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2x 400 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [Si02, 80 g, EtOAc/heptane] to e (S)—tert-butyl 1-(biphenylyl)—2- hydroxyethylcarbamate (609 mg). LCMS m/z 258.2 (M + H; loss of t—Bu)+, Rt 0.97 min. 1H NMR (400 MHz, CD30D) 8 ppm 7.62 - 7.56 (m, 4 H), 7.45 - 7.37 (m, 4 H), 7.34 - 7.2(m, 1 H), 4.69 (t, J = 5.8 Hz, 1 H), 3.76 - 3.63 (m, 2H), 1.44 (br. s., 9 H) Step 3: Preparation of (S)amino(biphenylyl)ethano| To a solution of (S)—tert-butyl 1-(biphenylyl)hydroxyethylcarbamate (608 mg, 1.940 mmol) in MeOH (3 mL) was added HCI (4M in dioxane, 8 mL) at room temperature. The mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL)/water (1.0 mL) and stirred with NaHCO3 for 1 hour. The mixture was ed off and rinsed with DCM. The filtrate was dried over sodium sulfate, filtered off and concentrated under reduced re providing (S)—2-amino(biphenyl- 4-yl)ethanol (171 mg) as a white solid. LCMS m/z 214.2 (M + H)+, Rt 0.58 min.
Step 4: Preparation of (S)(bipheny|y|)oxazo|idinone To a solution of (S)amino(biphenylyl)ethanol (171 mg, 0.802 mmol) in THF (12 mL) under argon atmosphere was added CDI (132 mg, 0.814 mmol). The solution was stirred at room temperature for 2 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (40 mL) and extracted with EtOAc (2x 30 mL). The combined organic layers were washed with 0.5M aqueous HCI solution (30 mL), brine (40 mL), dried over sodium sulfate, ed off and concentrated under reduced re. The residue was dissolved in DCM and concentrated under rduced pressure to provide crude (S)—4- (biphenylyl)oxazolidinone (156 mg) as a beige solid, which was used without r purification. LCMS m/z 240.1 (M + H)+, Rt 0.80 min. 1H NMR (400 MHz, CD30D) 8 ppm 4.19 (dd, J=8.61, 6.50 Hz, 1 H) 4.80 (t, J=8.73 Hz, 1 H) 5.05 (dd, J=8.78, 6.48 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.39 - 7.54 (m, 4 H) 7.55 - 7.71 (m, 4 H).
Intermediate P: 4,4,5,5-tetramethyloxazolidinone HN 0 Step 1: Preparation of Methyl 2-(tert-butoxycarbonylamino)methylpropanoate To a solution of 2-(tert-butoxycarbonylamino)methylpropanoic acid (10.03 g, 49.4 mmol) in MeOH/DCM (60mL/140mL) at room ature was added drop wise (trimethylsilyl)diazomethane (37.0 mL, 74.0 mmol). The reaction e was stirred for minutes. Acetic acid was added drop wise to quench (trimethylsi|y|)diazomethane.
The reaction mixture was concentrated under reduced pressure to afford the desired product as a white solid (10.56 g). LCMS m/z 240.2 (M + Na)+, Rt 0.71 min.
Step 2: Preparation of tert-butyl 3-hydroxy-2,3-dimethylbutanylcarbamate To a solution of methyl 2-(tert-butoxycarbonylamino)methylpropanoate (10.56 g, 48.6 mmol) in THF (300mL) at 0 °C was added drop wise methylmagnesium bromide (64.8 mL, 194 mmol). Cold bath was d after 1 hour. The on was stirred at 20 °C for 4 hours. The reaction was cooled back 0 °C and quenched with saturated NH4C| solution (10mL). The reaction mixture was then allowed to warm to room temperature, and diluted with EtOAc (100mL) and water (50mL). The phases were separated and the aqueous layer was extracted with EtOAc (2x100mL). The combined organics were then dried (Na2804) and concentrated. The e was purified via silica gel flash chromatography (0-20% EtOAc-Hexanes) to afford the desired product as a white solid (9.02 g). LCMS m/z 240.1 (M + Na)+, Rt 0.78 min.
Step 3: Preparation of 4,4,5,5-tetramethyloxazolidinone To tert-butyl 3-hydroxy-2,3-dimethylbutanylcarbamate (10.02 g, 46.1 mmol) in THF (300 ml) was added portion wise potassium 2-methylpropanolate (7.24 g, 64.6 mmol).
The reaction was stirred for five hours and ed with HCI (1M, 66mL) to pH=2. The reaction mixture was then concentrated under vacuum to about one third of the volume, and diluted with water (50mL). The aqueous layer was then extracted with DCM (3x100mL). The combined organic was washed with brine (50mL), dried (Na2804) and concentrated to give crude product as a light tan oil (6.25 g). LCMS m/z 144.1 (M + H)+, Rt 0.42 min.
The Intermediates in Table 2b were prepared by a method similar to the one described for the preparation of Intermediate P.
Table 2b.
Intermediate: Name Q: (4S)—4-isopropy|—5- MS m/z (M + H)+ methyloxazolidinone 144.4, Rt 0.47 min R: 4,4,5-trimethyloxazolidin MS m/z (M + H)+ one 130.4, Rt 0.36 min 8: 4,4-dimethyloxazolidinone MS m/z (M + H)+ 116.0, Rt 0.28 min Intermediate 1: (2-ch|oropyrimidiny|)pheny|oxazo|idinone ClPANEL,N A solution of (R)—4-pheny|oxazo|idinone 4 g, 18.07 mmol) and 2,4- dichloropyrimidine 2 g, 21.39 mmol, 1.184 equiv) in DMF (30 mL) was treated with NaH (95 %, 0.4773 g, 18.89 mmol, 1.046 equiv), then the resulting mixture (yellow to red cloudy) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (200 mL), washed with sat. NH4C| (75 mL) and 4% aqueous NaCI (2 x 100 mL), dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)—3-(2-chIoropyrimidiny|)pheny|oxazo|idin one (2.7020 g, white sticky solid) in 46.9% yield. 1H NMR (400 MHz, CDgOD) 8 8.47 (d, J = 5.6 Hz, 1 H), 8.18 (d, J = 6.1 Hz, 1 H), 7.38 — 7.30 (m, 5 H), 5.81 (dd, J = 8.6, 3.5 Hz, 1 H), 4.88 (t, J = 8.6 Hz, 1 H), 4.37 (dd, J = 8.6, 3.5 Hz, 1 H); MS m/z 276.4 (M + H)+.
The Intermediates in Table 3 were prepared by a method similar to the one described for the preparation of Intermediate 1.
Table 3.
Intermediate 2 Intermediate 3 ediate 4 I Intermediate 6 Intermediate 7 Intermediate 8 Intermediate 9 Intermediate 11 Intermediate 14 Intermediate 15 Intermediate 16 WO 46136 Intermediate 23 Intermediate 24 Intermediate 26 Intermediate 27 Intermediate 28 Table 4. Chemical name, NMR chemical shifts and LCMS signal for each ediate listed in Table 3.
Intermediate: Name 1H NMR 400 MHz 8 ppm LCMS 2: (S)(2-chloropyrimidin (CDCI3) 8.47 (d, J = 6.1 Hz, 1 H), 8.18 MS m/z yl)—4-phenyloxazolidinone (d, J = 5.7 Hz, 1 H), 7.39 — 7.29 (m, 5 276.5 (M + H), 5.81 (dd, J = 8.6, 3.5 Hz, 1 H), 4.88 H)+ (t, J = 8.8 Hz, 1 H), 4.37 (dd, J = 8.8, 3: 3-(2-chloropyrimidin ) 8.48 (d, J = 8.1 Hz, 1 H), MS m/z yl)oxazolidinone 8.16 (d, J = 6.1 Hz, 1 H), 4.54 (t, J = 200.4 (M + 7.8 Hz, 2 H 4.22 , t, J = 8.1 Hz, 2 H H + 4: (S)—4-benzyl(2- (CD30D) 8.52 (d, J = 6.1 Hz, 1 H), MS m/z chloropyrimidinyl)oxazolidin- 8.15 (d, J = 6.1 Hz, 1 H), 7.32 — 7.22 290.3 (M + 2-one (m, 5 H), 5.07 — 5.02 (m, 1 H), 4.48 — H)+ 4.37 (m, 2 H), 3.30 — 3.27 (m, 1 H), 3.06 dd, J = 13, 8.1 Hz, 1 H : (R)—4-benzyl(2- (CD30D) 8.51 (d, J = 5.8 Hz, 1 H), MS m/z chloropyrimidinyl)oxazolidin- 8.13 (d, J = 5.6 Hz, 1 H), 7.31 — 7.21 290.3 (M + 2-one (m, 5 H), 5.06 — 4.98 (m, 1 H), 4.45 — H)+ 4.34 (m, 2 H), 3.30 — 3.25 (m, 1 H), 3.04 dd, J = 14, 8.1 Hz, 1 H 6: (S)(2-chloropyrimidin (CD30D) 8.50 (d, J = 5.9 Hz, 1 H), MS m/z yl)isopropyloxazolidinone 8.17 (d, J = 5.8 Hz, 1 H), 4.83 — 4.78 242.6 (M + (m, 1 H), 4.48 — 4.43 (m, 2 H), 2.56 H)+ (dtd, J = 14, 7.0, 3.8 Hz, 1 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.1 Hz, 3 7: (S)—4-benzhydryl(2- (CD30D) 8.41 (d, J = 5.8 Hz, 1 H), MS m/z chloropyrimidinyl)oxazolidin- 8.01 (d, J = 5.8 Hz, 1 H), 7.35 — 7.26 366.1 (M + 2-one (m, 3 H), 7.24 — 7.12 (m, 7 H), 5.86 — H)+ .70 m, 1 H,4.74 d,J=7.1Hz,1H 4.64 (t, J = 8.5 Hz, 1 H), 4.45 (dd, J = 9.1, 2.0 Hz, 1 H 8: (4R, (2- (CD30D) 8.52 (d, J = 6.1 Hz, 1 H), MS m/z chloropyrimidinyl)—4-methy|— 8.20 (d, J = 6.1 Hz, 1 H), 7.48 — 7.38 290.3 (M + -phenyloxazolidinone (m, 5 H), 5.92 (d, J = 7.6 Hz, 1 H), 5.15 H)+ (quin, J = 6.8 Hz, 1 H), 0.98 (d, J =6.6 9: (4S,5R)—3-(2- ) 8.52 (d, J = 6.1 Hz, 1 H), MS m/z chloropyrimidinyl)—4-methy|— 8.20 (d, J = 6.1 Hz, 1 H), 7.48 — 7.38 290.3 (M + -phenyloxazolidinone (m, 5 H), 5.92 (d, J = 7.6 Hz, 1 H), 5.15 H)+ (quin, J = 6.7 Hz, 1 H), 0.98 (d, J =6.6 : (S)—3-(2-chIoropyrimidin (CD30D) 8.48 (d, J = 5.8 Hz, 1 H), MS m/z isopropy|—5,5- 8.20 (d, J = 5.8 Hz, 1 H), 4.63 (d, J = 270.1 (M + dimethyloxazolidinone 3.1 Hz, 1 H), 2.29 (dtd, J = 14, 7.0, 3.1, H)+ 1 H), 1.60 (s, 3 H), 1.47 (s, 3 H), 1.05 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 11: (S)—3-(2-chIoropyrimidin (CD30D) 8.48 (d, J = 5.8 Hz, 1 H), MS m/z y|)—5,5-dimethy|—4- 8.25 (d, J = 5.8 Hz, 1 H), 7.39 — 7.30 304.3 (M + phenyloxazolidinone (m, 3 H), 7.22 (br s, 2 H), 1.67 (s, 3 H), H)+ 1.04 s, 3 H 12: (S)—3-(2-chIoropyrimidin (CD30D) 8.49 (d, J = 5.9 Hz, 1 H), MS m/z y|)isobuty|oxazo|idinone 8.13 (d, J = 5.9 Hz, 1 H),4.83 (ddt, J = 256.3 (M + , 7.6, 2.9 Hz, 1 H), 4.58 — 4.54 (m, 1 H)+ H), 4.31 (dd, J = 8.8, 2.8 Hz, 1 H), 1.87 — 1.81 (m, 1 H), 1.75— 1.65 (m, 1 H), 1.62 — 1.55 (m, 1 H), 1.05 (d, J = 6.5 Hz,3H,0.99 d,J=6.5Hz,3H 13: (R)(2-chIoropyrimidin (CD30D) 8.48 (d, J = 5.8 Hz, 1 H), MS m/z y|)isobuty|oxazo|idinone 8.12 (d, J = 6.0 Hz, 1 H),4.87 — 4.79 256.3 (M + (m, 1 H), 4.57 (t, J = 8.6 Hz, 1 H), 4.31 H)+ (dd, J = 8.6, 2.5 Hz, 1 H), 1.87 — 1.81 (m, 1 H), 1.75 — 1.65 (m, 1 H), 1.62 — 1.56 (m, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.99 d, J = 6.6 Hz, 3 H 14: (S)—4-tert-buty|—3-(2- (CD30D) 8.50 (d, J = 5.9 Hz, 1 H), MS m/z chloropyrimidiny|)oxazo|idin- 8.12 (d, J = 5.9 Hz, 1 H), 4.94 (dd, J = 256.4 (M + 2-one 7.6, 1.5 Hz, 1 H), 4.54 (dd, J = 9.1, 1.5 H)+ Hz, 1 H), 4.46 — 4.42 (m, 1 H), 0.95 (s, : (4R,5S)—3-(2- (CD30D) 8.52 (d, J = 5.9 Hz, 1 H), MS m/z ch|oropyrimidiny|)—4,5- 8.33 (d, J = 5.9 Hz, 1 H), 7.14 — 7.05 352.4 (M + diphenyloxazolidinone (m, 8 H), 6.93 — 6.91 (m, 2 H), 6.18 — H)+ 6.11 m, 2 H 16: )—3-(2- (CD30D) 8.52 (d, J = 5.9 Hz, 1 H), MS m/z ch|oropyrimidiny|)—4,5- 8.33 (d, J = 5.9 Hz, 1 H), 7.14 — 7.05 352.3 (M + diphenyloxazolidinone (m, 8 H), 6.93 — 6.91 (m, 2 H), 6.18 — H)+ 6.11 m, 2 H 17: (4S,5R)—3-(2- (CD30D) 8.47 (d, J = 5.9 Hz, 1 H), MS m/z chloropyrimidinyl)—5-methy|— 8.25 (d, J = 5.9 Hz, 1 H), 7.40 — 7.31 290.4 (M + 4-phenyloxazolidinone (m, 3 H), 7.21 (d, J = 7.0 Hz, 2 H), 5.80 H)+ (d, J = 7.5 Hz, 1 H), 5.18 — 5.12 (m, 1 ,1.02 d,J=6.5Hz,3H- 18: S benz | 2- CDCI3 8.45 d, J :58 Hz, 1 H , 8.16 ch|oropyrimidiny|)—5,5- (d, J = 5.8 Hz, 1 H), 7.37 — 7.28 (m, 4 318.1 (M + dimethyloxazolidinone H), 7.25 — 7.21 (m, 1 H), 4.87 (dd, J = H)+ 9.0, 4.5 Hz, 1 H), 3.24 (dd, J = 15, 4.5 Hz, 1 H), 2.97 (dd, J = 14, 9.0 Hz,1 19: (S)—3-(2-ch|oropyrimidin (CDCI3) 8.76 — 8.75 (m, 1 H), 8.62 (d, J MS m/z (pyridiny|)oxazo|idin = 3.5 Hz, 1 H), 8.47 (d, J = 5.8 Hz, 1 277.4 (M + one H), 8.16 (d, J = 5.8 Hz, 1 H), 7.74 (dt, J H)+ = 8.0, 2.0 Hz, 1 H), 7.35 (dd, J = 7.8, 4.8 Hz, 1 H), 5.83 (dd, J = 8.8, 3.8 Hz, 1 H), 4.90 (t, J = 9.0 Hz, 1 H), 4.50 (dd, J = 9.0, 3.5 Hz, 1 H : 3-(2-chloropyrimidiny|)- ) 8.44 (d, J = 5.8 Hz, 1 H), 8.25 HRMS(B) 4-(4-methoxypheny|)-5,5- (d, J = 5.8 Hz, 1 H), 7.13 (br d, J = 7.0 m/z 334.0954 dimethyloxazolidinone Hz, 2 H), 6.89 (d, J = 9.0 Hz, 2 H), (M + H)+ .39 (s, 1 H), 3.82 (s, 3 H), 1.67 (s, 3 21: (S)—3-(2-ch|oropyrimidin (CDCI3) 8.62 — 8.60 (m, 1 H), 8.45 (d, J MS m/z y|)(pyridiny|)oxazo|idin = 5.8 Hz, 1 H), 8.22 (d, J = 5.8 Hz, 1 277.0 (M + one H), 7.73 (td, J = 7.7, 1.8 Hz, 1 H), 7.43 H)+ (d, J = 7.5 Hz, 1 H), 7.29 — 7.26 (m, 1 H), 5.85 (dd, J = 8.5, 3.5 Hz, 1 H), 4.82 (t, J = 8.8 Hz, 1 H), 4.64 (dd, J = 8.8, 22: (S)—3-(2-ch|oropyrimidin (CDCI3) 8.72 — 8.70 (m, 1 H), 8.52 (d, J MS m/z y|)(pyridiny|)oxazo|idin = 5.8 Hz, 1 H), 8.20 (d, J = 5.8 Hz, 1 276.9 (M + one H), 7.43 — 7.42 (m, 1 H), 5.81 (dd, J = H)+ 8.8, 3.8 Hz, 1 H), 4.91 (t, J = 9.0 Hz, 1 H 4.44 1 H , dd, J = 9.3, 3.8 Hz, 23: (2-ch|oropyrimidin (CDCI3) 8.44 (d, J = 5.8 Hz, 1 H), 8.13 MS m/z y|)methy| (d, J = 5.8 Hz, 1 H), 7.41 — 7.28 (m, 5 289.9 (M + phenyloxazolidinone H), 4.46 (d, J = 8.5 Hz, 1 H), 4.38 (d, J H)+ =8.5Hz, 1 H ,2.23 s,3H 24: (S)—3-(2-ch|oro (CDCI3) 8.06 (s, 1 H), 4.83 — 4.77 (m, 1 MS m/z methylpyrimidinyl)—4- H), 4.44 — 4.34 (m, 2 H), 2.65 — 2.55 255.8 (M + pyloxazolidinone (m, 1 H), 2.53 (s, 3 H), 1.00 (d, J = 8 H)+ Hz,3H,0.88 d,J=8Hz,3H : (S)—3-(2-ch|oro (CDCI3) 8.50 (s, 1 H), 5.01 — 4.96 (m, 1 MS m/z methylpyrimidinyl)—4- H), 4.53 (t, J = 9.0 Hz, 1 H), 4.28 (t, J = 255.9 (M + isopropyloxazolidinone 8.8 Hz, 1 H), 2.35 (s, 3 H), 2.16 (td, J = H)+ 7.0 Hz, J = 4.5 Hz, 1 H), 0.93 (d, J = 7.0 Hz, 3 H , 0.84 d, J = 6.5 Hz, 3 H 26: (S)—3-(2-ch|oro (DMSO-da) 8.95 (d, J = 3.0 Hz, 1 H), MS m/z fluoropyrimidiny|) 4.79 — 4.73 (m, 1 H), 4.58 (t, J = 9.0 259.9 (M + isopropyloxazolidinone Hz, 1 H), 4.41 (dd, J = 8.5 Hz, J = 6.5 H)+ Hz, 1 H), 2.24 — 2.16 (m, 1 H), 0.86 (d, J = 7.0 Hz, 3 H), 0.78 (d, J = 6.5 Hz, 3 27: (S)—3-(2,5- (DMSO-ds) 9.01 (s, 1 H), 4.81 (ddd, J MS m/z dich|oropyrimidiny|)—4- = 9.1 Hz, J = 7.8 Hz, J = 4.3 Hz, 1 H), 274.2 (M - H)‘ isopropyloxazolidinone 4.59 (t, J = 8.8 Hz, 1 H), 4.38 — 4.33 (m, 1H), 2.06 (td, J = 7.0 Hz, J = 4.3 Hz, 1 H), 0.84 (d, J = 6.8 Hz, 3 H), 0.78 d, J = 6.8 Hz, 3 H 28: R 2-chlorop rimidin CDCI3 8.20 d, J = 5.8 Hz, 1 H , 8.01 (d, J = 5.8 Hz, 1 H), 7.16 — 7.07 (m, 3 303.9 (M + H), 6.98 — 6.96 (m, 2 H), 5.19 (s, 1 H), H)+ 29: 3-(2-chloropyrimidinyl)— MS m/z 4,4-dimethyloxazolidinone 228.3 (M + : (R)(2-chloropyrimidin MS m/z y|)methyl (d, J = 5.8 Hz, 1 H), 7.40 — 7.36 (m, 4 289.9 (M + oxazolidinone H), 7.35 — 7.28 (m, 1 H), 4.45 (d, J = H)+ 8.6 Hz, 1 H), 4.38 (d, J = 8.6 Hz, 1 H), Intermediate 31: (S)—3-(2-fluoropyrimidinyl)isopropyloxazolidinone A solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and (S)—4-isopropyloxazolidin one (5.3 g 41 mmol) in 30 mL DMF was cooled to 0 °C under N2 here. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added. Bubbling exotherm observed. Internal temp was kept below 5 °C. After 5 minutes, cold bath was removed. Reaction mixture (a sandy sion) was allowed to warm to room temp and stir 18 h. The reaction mixture was diluted with water (100 mL) and extracted with (3 x 75 mL) EtOAc. Organic layer was washed with 50 mL each water, and brine. Dried over Na2804, and concentrated on silica gel in vacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g (S)—3-(2-fluoropyrimidinyl)isopropyloxazolidinone (IV) as a lline white solid (33%). 1H NMR (400 MHz, CDCI3) 5 8.50 (dd, J = 5.8, 2.2 Hz, 1H), 8.19 (dd, J = 5.8, 3.8 Hz, 1H), 4.79 (dt, J = 8.1, 3.5 Hz, 1H), 4.48 — 4.34 (m, 2H), 2.64 (heptd, J = 7.0, 3.6 Hz, 1H), 1.01 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H). MS m/z 471.8 and 471.8 (M + H)+.
The Intermediates in Table 4b were prepared by a method similar to the one described for the preparation of Intermediate 1 and 31.
WO 46136 Table 4b.
Intermediate 32 Intermediate 33 Intermediate 34 Intermediate 35 Intermediate 37 Intermediate 44 Table 4c. Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed in Table 4b. 32: 3-(2-fluoropyrimidin (CDCI3) 8.51 (dd, J = 5.8, 2.0 Hz, 1 H), MS m/z yl)oxazo|idinone 8.17 (dd, J = 5.8, 2.0 Hz, 1 H), 4.61 - 184.0 (M + 4.57 (m, 2 H), 4.31 - 4.27 (m, 2 H) H) 33: (R)—3-(2-chIoropyrimidin (CDCI3) 8.45 (d, J = 5.8 Hz, 1 H), 8.12 MS m/z (4-f|uorophenyl)—4- (d, J = 5.8 Hz, 1 H), 7.40 — 7.35 (m, 2 308.0 (M + methyloxazolidinone H), 7.10 — 7.04 (m, 2 H), 4.40 — 4.37 H)+ .22 s,3H 34: 1-(2-ch|oropyrimidiny|)— (CDCI3) 8.48 (d, J = 5.8 Hz, 1 H), 8.12 3-oxaazaspiro[4.4]nonan (d, J = 5.8 Hz, 1 H), 4.22 (s, 2 H), 2.66 254.1 (M + one — 2.59 (m, 2 H), 2.22 — 2.14 (m, 2 H), 1.75— 1.62 m, 4 H : (4S)—3-(2-chloropyrimidin MS m/z (M + y|)i80pr0pyI H)+ 256.2, Rt meth loxazolidinone 0.87 min 36: (4S)—3-(2-ch|oro—5- MS m/z (M + fluoropyrimidinyl)—4- H)+ 274.1, Rt isopropylmethyloxazolidin 0.82 min 37: 3-(2-chloropyrimidinyl)— MS m/z (M + 4,4,5,5-tetramethyloxazolidin- H)+ 256.1, Rt 2-one 0.85 min 38: 3-(2-chloro—5- MS m/z (M + fluoropyrimidinyl)-4,4,5,5- H)+ 274.1, Rt tetrameth loxazolidinone 0.83 min 39: 3-(2-chloropyrimidinyl)— MS m/z (M + 4,4,5-trimethyloxazolidinone H)+ 242.1, Rt 0.81 min 40: 3-(2-chloro MS m/z (M + fluoropyrimidinyl)—4,4,5- H)+ 260.1, Rt h loxazolidinone 0.77 min 41: 1-(2-chloro ) 8.47 (d, J = 2 Hz, 1 H), 4.28 MS m/z (M + fluoropyrimidinyl)—3-oxa (s, 2 H), 2.54 — 2.44 (m, 2 H), 2.11 — H)+ 272.4 azaspiro[4.4]nonanone 1.99 (m, 2 H), 1.90 — 1.82 (m, 2 H), 1.72— 1.61 m, 42 H 42: 3-(2-chloropyrimidinyl)— MS m/z (M + 4,4-dimethyloxazolidinone H)+ 228.0, Rt 0.73 min 43: 3-(2-chloro MS m/z (M + fluoropyrimidinyl)—4,4- H)+ 246.0, Rt dimeth loxazolidinone 0.70 min 44: 3-(2-chloro MS m/z (M + pyrimidinyl)oxazolidin- H)+ 218.0, Rt 2-one 0.47 min Intermediate 46: (S)(biphenyly|)(2-chloropyrimidinyl)oxazo|idinone To a solution of 2,4-dichloropyrimidine (46.5 mg, 0.312 mmol) and (S)(biphenyl y|)oxazo|idinone (74.7 mg, 0.312 mmol) in DMF (700 uL) was added NaH (60%wt., .49 mg, 0.437 mmol) in two portions within ~5 min [Caution: exotherm; gas development] at room temperature (water bath). The reaction mixture was stirred for 1.5 hour. The e was diluted with EtOAc (25 mL), stirred for 5 min and then diluted slowly with diluted brine (10 mL; 1:1 brine/water). The mixture was poured into diluted brine (40 mL) and EtOAc (25 mL). The separated organic phase was washed with diluted brine (3x 40 ml), dried over Na2804, filtered off and concentrated under reduced pressure. The e was purified by column chromatography [Si02, 40 g, EtOAc/heptane] to provide (biphenylyl)(2-chloropyrimidinyl)oxazolidin one (49.5 mg). LCMS m/z 352.2 (M+ H)+, Rt 1.06 min.
Intermediate 47 : 3-(2-chloropyrimidinyl)phenyl-1,8-dioxa azaspiro[4.5]decanone ELLA/IL ON N CI To a e of 4-phenyl-1,8-dioxaazaspiro[4.5]decanone (300 mg, 1.286 mmol) and 2,4-dichloropyrimidine (192 mg, 1.286 mmol) in DMF (7 mL) under argon was added NaH (60%wt., 67.9 mg, 2.83 mmol) in two ns. The mixture was stirred for ~1 hour.
The reaction mixture was carefully poured into ice-colled 0.25N aqueous HCI solution.
DCM and s NaHCO3 solution were added. The ted aqueous layer was extracted with DCM (3x) and ethyl acetate (1x). The organic layers (DCM and ethyl acetate containing layers ndently) were washed with brine, dried over Na2804 and filtered off. The organic layers were combined and concentrated under reduced pressure providing crude 3-(2-chloropyrimidinyl)—4-phenyl-1,8-dioxa azaspiro[4.5]decanone (330 mg) as a yellowish liquid, which was ly used in the next reaction without further purification. LCMS m/z 346.1 (M + H)+, Rt 0.83 min.
Intermediate 48 : 7-(2-chloropyrimidinyl)phenyl-2,5-dioxa azaspiro[3.4]octanone 0%ka...O / N Prepared using similar methods as described above for 3-(2-chloropyrimidinyl)—4- phenyl-1,8-dioxaazaspiro[4.5]decanone, but starting with oxetanone.
LCMS m/z 318.1 (M + H)+, Rt 0.78 min.
Intermediate 50: 3-(2-chloro—5-fluoropyrimidinyl)—5,5-dimethyloxazolidinone Step 1 A solution of 2,4-dichlorofluoropyrimidine (2 g, 11.98 mmol) in acetonitrile (10 mL) was cooled to -40 °C, avoiding freezing. To this solution was added diisopropylamine (3.82 mL, 21.88 mmol) followed by 1-aminomethylpropanol (1.5 g, 16.83 mmol). The reaction mixture was removed from the cooling bath, warmed to room ature and allowed to stir overnight (~18 hours). Solvents were removed in vacuo and the residue was taken up in a minimum of dichloromethane (~1.5-2 mL) and diluted with heptane until slightly cloudy.This mixture was loaded onto a 40 gram BioRad silica gel cartridge.
Purification by flash chromatorgraphy (Analogix System, 20 min gradient, 0-25% methanol/dichloromethane, 40 mL/min.) provided 1-(2-chlorofluoropyrimidin ylamino)methy|propanol as a white solid. LCMS m/z 220.1, 221.8 (M + H)+, Rt 0.49 min.
Step 2 To a suspension of 1-(2-chlorofluoropyrimidinylamino)methylpropanol (400 mg, 1.82) in DCM/ethylacetate (5 mL) was added 2,6-lutidine (1 mL, 8.59 mmol). The reaction was cooled to -78°C and sgene (292 mg, 0.983 mmol) was added in a single portion. The reaction was removed from the cooling bath and allowed to warm to room temperature. The reaction had a pinkish coloration at this time. LCMS indicated ption of starting material and conversion the intermediate acyl chloroformate adduct of 1-(2-ch|orofluoropyrimidinylamino)methy|propanol. The reaction was sealed and stirred overnight. The reaction was stirred at room ature overnight to provide only partial closure of the intermediate acyl formate to the cyclic carbamate. The on (sealed) was then heated at 60°C for ~4 hours until intermediate acyl chloroformate was consumed. Reaction was cooled to room temperature, d with DCM (~50 mL) and washed with water (1x50 mL) and sat. NaHCO3 (1x50 mL). Aqueous layers were back extracted with DCM (~50 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The solid was dissolved in DCM (~15 mL) and celite (~4 gram) was added. The mixture was concentrated and dried in vacuo to provide a solid pre-load for subsequent cation. cation by flash chromatography(Analogix System, 80 gram silica gel column, 25 min. gradient, 0-25% methanol/dichloromethane, 40 mL/min) provided 3-(2-chlorofluoropyrimidinyl)—5,5- dimethyloxazolidinone as a white solid. 1H NMR (400 MHz, METHANOL-d4) 8 ppm 1.58 (s, 8 H) 4.02 (s, 2 H) 8.59 (d, J=3.13 Hz, 1 H): LCMS m/z (M + H)+ 246.1, 2478.0, Rt 0.61 min The Intermediates in Table 4d were prepared by methods similar to the one described for the ation of Intermediate 50.
Table 4d.
Intermediate 51 Intermediate 52 Table 4e. Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed in Table 4d.
Intermediate: Name 1H NMR (400 MHz, METHANOL-d4) 8 LCMS 51: 3-(2-chIorofluoropyrimidin- 1.52 (d, J=6.26 HZ, 3 H) 3.89 (dd, MS m/Z (M + 4-y|)methy|oxazolidinone J=9.78, 7.43 Hz, 1 H) 4.26 (dd, J=9.78, H)+ 232.0, 7.43 Hz, 1 H) 4.90 - 4.98 (m, 1 H) 8.58 233.9, Rt (d, J=2.74 Hz, 1 H) 0.52 min 52: 6-(2-chIorofluoropyrimidin- 0.90 - 1.08 (m, 2 H) 1.18 - 1.37 (m, 2 MS m/Z (M + 4-y|)oxaazaspiro[2.4]heptan- H) 4.31 (s, 2 H) 8.61 (d, J=3.13 Hz, 1 H)+ 244.0, -one H) 245.8, Rt 0.61 min Intermediate 53: 3-(2,6-dichIoropyrimidinyl)—4,4-dimethyloxazolidinone Cl N N O A solution of 4,4-dimethyloxazolidinone (0.103 g, 0.895 mmol) and 2,4,6- trichloropyrimidine (0.181 g, 0.984 mmol, 1.10 equiv) in DMF (3 mL) was treated with NaH (60 %, 0.0429 g, 1.07 mmol, 1.2 equiv), then the resulting mixture w) was stirred at room ature for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCI (2 x 20 mL), dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided3- (2,6-dichIoropyrimidinyl)-4,4-dimethyloxazolidinone (0.146 g, white solid) in 62.3% yield. 1H NMR (300 MHz, CDCI3) 8 8.14 (s,1 H), 4.16 (s, 2 H), 1.74 (s, 9H); LCMS m/z 261.9 (M + H)+, Rt 0.91 min.
The Intermediates in Table 4f were prepared by a method similar to the one described for the preparation of ediate 53.
Table 4f.
Intermediate 54 Intermediate 55 Table 4g. Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed in Table 4f. ediate: Name 1H NMR 400 MHz 5 ppm 54: 3-(2,6-dichloropyrimidin (CDCI3) 8.20 (s, 1 H), 4.59 (t, J = 8.0 MS m/z zolidinone Hz, 2 H), 4.29 (t J = 8.0 Hz, 2 H) 234.0 (M + H)+, Rt 0.67 55: 3-(2,6-difluoropyrimidin (CDCI3) 7.68 (d, J = 2.0 Hz, 1 H), 4.16 MS m/z y|)-4,4-dimethyloxazolidin (s, 2 H), 1.74 (s, 6 H) 230.1 (M + one H)+, Rt 0.79 Intermediate 56 : (S)-methyl 4-(1-(tert-butoxycarbonylamino)ethyl)benzoate HNJLOJ<o To a solution of (S)-methyl 4-(1-aminoethyl)benzoate (4.9 g, 22.7 mmol) in DCM (114 mL) was added di-tert-butyl dicarbonate (5.95 g, 27.3 mmol) and triethylamine (6.97 mL, 50 mmol). The solution was stirred for 16 h at room temperature then washed with water and brine. The organic layer was dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided (S)-methyl 4-(1-(tertbutoxycarbonylamino )ethyl)benzoate as a white solid (6.35 g, 100% yield). 1H NMR (400 MHz, CDCI3) 6 8.04 — 7.96 (m, 2H), 7.40 — 7.33 (m, 2H), 4.83 (s, 1H), 3.91 (s, 3H), 1.43 — 1.23 (m, 12H); MS m/z 224.0 (M - 56 + H).
Intermediate 57 : (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate O J< HNJJ\O -361 To a cooled (0 °C) solution of (S)-methyl 4-(1-(tert-butoxycarbonylamino)ethyl)benzoate (6.35 g, 22.7 mmol) in THF (114 mL) was added a solution of LAH in THF (2.0 M, 13.64 mL, 27.3 mmol) and the resulting mixture was d at room temperature for 40 min.
The reaction mixture was quenched by addition of a 1N NaOH solution until gas evolution ceased. The on mixture was filtered, washed with EtOAc. After separation, the aqueous phase was washed with EtOAc (2 x 150 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 100%) provided (S)-tert-butyl 1-(4- (hydroxymethyl)phenyl)ethylcarbamate as a white solid (5.01 g, 84% yield). 1H NMR (400 MHz, CDCI3) 6 7.35 — 7.23 (m, 4H), 4.80 — 4.71 (m, 1H), 4.67 (s,2H), 2.04 (bs,1H), 1.47 — 1.37 (m, 12H); MS m/z 196.0 (M - 56 + H).
Intermediate 58: (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate HNJkOJ< To a solution of (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate (503 mg, 2 mmol) in DCM (10 mL) was added methanesulfonyl chloride (275 mg, 2.4 mmol) and triethylamine (0.56 mL, 4 mmol). The on was stirred for 16 h at room temperature then washed with water and brine. After tion, the organic phase was dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) ed rt-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate as a white solid (254 g, 47.1% yield). 1H NMR (400 MHz, CDCI3) 6 7.40 — 7.24 (m, 4H), 4.79 (s, 1H), 4.58 (s, 2H), 1.50 — 1.30 (br m, 12H); MS m/z 214.0 (M - 56 + H).
Intermediate 59: (S)-tert—butyl 1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- y|)methy|)phenyl)ethylcarbamate N\N Wick 4635*\ A solution of (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate (127 mg, 0.47 mmol), 8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (91 mg, 0.56 mmol) and DIPEA (183 mg, 1.41 mmol) in DMSO (2.3 mL) was heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). After separation, the aqueous phase was washed with EtOAc (2 x 15 mL). Combined organics were dried over , filtered and concentrated. The crude product was used to next step without further purification.
MS m/z 358.3 (M + H) Intermediate 60: (S)—1-(4-((5,6-dihydro—[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methyl)phenyl)ethanamine (Wk NH2 ”80* To a solution of (S)-tert-butyl 1-(4-((5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methyl)phenyl)ethylcarbamate (168 mg, 0.47 mmol) in DCM (2 mL) was added TFA (2 mL, 26 mmol) slowly at -78 °C. The on was stirred at room temperature for 1 h then concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP- carbonate resin (3.28 mmol/g, e) for 1 hour at room temperature. The resin was removed by tion and washed (2 x 5 mL) with DCM. The filtrate was concentrated and the crude residue was used to next step without further purification.
MS m/z 258.2 (M + H).
Intermediate 61: (S)—4-(1-(tert-butoxycarbonylamino)ethy|)—2-f|uorobenzoic acid To a solution of (S)(1-aminoethyl)fluorobenzoic acid (5 g, 22.76 mmol) in water (66 mL) and THF (66 mL) was added di-tert-butyl dicarbonate (6.95 g, 31.9 mmol) and sodium carbonate (5.74 g, 68.3 mmol). The solution was stirred for 16 h at room temperature then THF was removed under reduced pressure. The aqueous solution was acidified with 1N HCI to pH 3-4 and extracted with EtOAc (3 x 60 mL). Combined organics were dried over Na2804, filtered and concentrated to give a white solid (1.94 g, .1% yield). The crude product was used to next step t further purification. 1H NMR (400 MHz, MeOD) 5 7.89 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 7.13 (dd, J = 12.0, 1.6 Hz, 1H), 4.70 (d, J = 7.1 Hz, 1H), 1.47 — 1.35 (m, 12H); MS m/z 282.0 (M - H).
Intermediate 62: (S)—tert-butyl luoro(methoxy(methyl)carbamoyl)phenyl) ethylcarbamate HNJJ\oJ<o A on of (S)—4-(1-(tert-butoxycarbonylamino)ethyl)—2-fluorobenzoic acid (1.416 g, 5mmol), N,O-dimethylhydroxylamine hydrochloride (732 mg, 7.5 mmol), HATU (2.85 g, 7.5 mmol) and DIPEA (3.49 mL, 20 mmol) in DMF (25 mL) was stirred at room temperature for 16 h. The on mixture was diluted with EtOAc and washed with water. After separation, the aqueous phase was washed with EtOAc (2 x 75 mL).
Combined cs were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-buty| 1-(3-fluoro- 4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate as a white solid (1.5 g, 92 % yield). 1H NMR (400 MHz, CDCI3) 5 7.40 (t, J = 7.4 Hz, 1H), 7.13 (dd, J = 7.8, 1.6 Hz, 1H), 7.04 (dd, J = 10.7, 1.6 Hz, 1H), 4.80 (br s, 1H), 3.56 (s, 3H), 3.34 (s, 3H), 1.50 — 1.29 (m, 12H); MS m/z 327.1 (M + H).
Intermediate 63 : (S)-tert-butyl luoroformylphenyl)ethylcarbamate HNJLOJ<o Procedure 1: To a cooled (0 °C) solution of (S)-tert—butyl 1-(3-fluoro (methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g, 3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18 mL, 18 mmol) and the resulting e was stirred at 0 °C for 20 min. The reaction mixture was quenched by addition of a saturated Na2804 solution until gas evolution ceased. The reaction mixture was extracted with EtOAc (2 x 100 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoroformylphenyl)ethylcarbamate as a white solid (760 mg, 79% yield).
Procedure 2: A solution of (S)-tert-butyl 1-(4-bromo—3-fluorophenyl)ethylcarbamate (318 mg, 1 mmol) in dry THF (5 mL) was cooled to -78 °C. BuLi (2.5 M, 840 uL, 2.1 mmol) was added dropwise and the resulting solution was stirred at -78 °C for 1 h. Then DMF (232 uL, 3.00 mmol) was added in one portion. The reaction was d for r 30 min at -78 °C then quenched with sat. NH4C| solution. The reaction was stirred at room temperature for another 30 min then d with EtOAc, washed with water and brine.
The separated organic was dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided (S)-tert-butyl 1-(3-fluoro formylphenyl)ethylcarbamate as a white solid (70 mg, 26.2% yield). 1H NMR (400 MHz, CDCI3) 6 10.31 (s, 1H), 7.87 — 7.80 (m, 1H), 7.20 (dd, J = 8.2, 1.3 Hz, 1H), 7.11 (dd, J = 11.5, 1.4 Hz, 1H), 4.80 (br s, 1H), 1.45 (br s, 12H); MS m/z 212.1 (M - 56 + H). ediate 64: rt-butyl 1-(3-fluoro((3,3,4-trimethylpiperazin yl)methyl)phenyl)ethylcarbamate WO 46136 (General procedure A for reductive amination) A solution of (S)-tert-butyl 1-(3-fluoroformylphenyl)ethylcarbamate (267 mg, 1 mmol) and 1,2,2-trimethylpiperazine ochloride (402 mg, 2 mmol) in THF (5 mL) was stirred at room temperature for 1 h and treated with sodium triacetoxyborohydride (848 mg, 4 mmol). The resulting mixture was stirred at room temperature for 16 h. The on mixture was quenched with saturated aqueous on of NaHCO3 (15 mL) and extracted with EtOAc (3 x 25 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (MeOH/CH2C|2 0 to 10%) provided (S)—tert-butyl 1-(3-fluoro((3,3,4-trimethylpiperaziny|)methyl)phenyl)ethylcarbamate as a white solid (186 mg, 49% yield). 1H NMR (400 MHz, CDCI3) 5 7.35 (t, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.9, 1.9 Hz, 1H), 6.95 (dd, J =11.1, 1.8 Hz, 1H), 4.77 (s, 1H), 3.49 (s, 2H), 2.56 (br s, 4H), 2.24 (br s, 5H), 1.42 (br s, 12H), 1.04 (s, 6H); MS m/z 380.4 (M + H).
Intermediate 65: tert-butyl (1S)—1-(4-((3,4-dimethylpiperazin yl)methyl)phenyl)ethylcarbamate A solution of (S)—tert-butyl 1-(4-formy|phenyl)ethylcarbamate (84.1 mg, 0.337 mmol) [obtained from (S)—1-(4-bromopheny|)ethanamine ing the procedure of Hashihayata, Takashi PCT lnt. Appl., 2008081910, 10 Jul 2008] and 1,2- dimethylpiperazine (86.3 mg, 0.756 mmol, 2.24 equiv) in THF (1.5 mL) was stirred at room temperature for 65 min and treated with sodium triacetoxyborohydride (277.2 mg, 1.308 mmol, 3.88 equiv). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 (15 mL) and ted with EtOAc (5 x 15 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (MeOH/CH2C|2 0 to 20%) provided tert-butyl (1S)—1-(4-((3,4-dimethylpiperazinyl)methyl)phenyl)ethy| carbamate (90.7 mg) in 34.5% yield. 1H NMR (400 MHz, CD30D) 6 7.29 (s, 4 H), 4.68 (br s, 1 H), 3.54 - 3.47 (m, 2 H), 3.37 (s, 1 H), 2.84 - 2.74 (m, 3 H), 2.38 (td, J = 12, 2.5 Hz, 1 H), 2.31 (s, 3 H), 2.28 - 2.22 (m, 2 H), 1.94 - 1.89 (m, 1 H), 1.40 (br s, 9 H), 1.38 (d, J = 6.9 Hz, 3 H), 1.06 (d, J = 6.3 Hz, 3 H); MS m/z 348.2 (M + H) Intermediate 66: (R,E)methyl-N-((3-methyl-1H-pyrazolyl)methylene)propane sulfinamide ,81V m5)N/ ”1 3-methyl-1H-pyrazolecarbaldehyde (2.03g, 18.44mmol) was dissolved in THF (30ml) and (R)—2-methylpropanesulfinamide (2.35, 19.39mmol) was added followed by Ti(OEt)4 (8.41mmol, 36.90mmol). The resulting reaction mixture was stirred at 80°C for 18h. LCMS shows mostly product. The reaction mixture was diluted with EtOAc (300 mL), washed with 4% aqueous NaCl (2 x 150, 2X50 mL). The ed aq. layers were back extracted with EtOAc ). The combined organic layers were washed with brine (100ml), dried over , filtered and concentrated. Purified by column chromatography (REDI 80g, EtOAc/heptane 20-100% over 33 min 100% for 7min.) to give title compound (2.25g, 10.55mmol). 1H NMR (400 MHz, MeOD) 5 8.55 (s, 1H), 2.53 (s, 3H), 1.25 (s, 9H). MS 214.2 m/z (M+H) Intermediate 67: (R)—2-methyl-N-((S)—1-(3-methyl-1H-pyrazolyl)ethyl)propane sulfinamide HN \{/ MyN/ (R,E)methyl-N-((3-methyl-1H-pyrazolyl)methylene)propanesulfinamide (2.25g, 10.55mmol) was dissolved in THF and cooled to DC. Methylmagnesium e (3M, 12.5ml, 37.5mmol) was added dropwise and the ing solution was stirred for 1h. lce bath was removed and the on was stirred for another 15h. r 2.5eq. of methylmagnesium bromide MeMgBr was added (at 0°C ). Not a lot of change by LCMS.
The on mixture was quenched with sat NH4C| and the aq. layer was washed with THF (2X). Combined organic layers washed with brine, dried over Na2804, filtered and concentrated to give title compound (1 .79g, 7.80mmol) 1H NMR (400 MHz, MeOD) 5 7.48 (s, 1H), 4.49 (qd, J = 6.7, 4.7 Hz, 1H), 2.26 (s, 3H), 1.57 (dd, J = 6.5, 1.3 Hz, 3H), 1.23 (s, 9H). MS 230.2 m/z (M+H) Intermediate 68: (R)—N-((S)—1-(1-benzylmethyl-1H-pyrazolyl)ethyl) methylpropanesulfinamide HN’S\¢/ Qfi N/ (R)—2-methyl-N-((S)—1-(3-methyl-1H-pyrazolyl)ethyl)propanesulfinamide (290mg, 1.26mmol) was dissolved in DMF (5ml) and added dropwise to a solution of Cs2CO3 (458mg, 1.41mmol) in DMF (4ml). The resulting reaction mixture was stirred at room temperature for 15min. benzylbromide (216mg, 1.26mmol) was added and the reaction was stirred at room temperature for 2h. LCMS shows mostly product with some ng pyrazole. Added another 0.1ml of BnBr and 135mg of Cs2C03. Stirred another 24H at he reaction mixture was diluted with EtOAc (300 mL), washed with 4% aqueous NaCl (2 x 150, 2X50 mL). The ed aq. layers were back extracted with EtOAc (100ml). The combined organic layers were washed with brine (100ml), dried over Na2804, filtered and concentrated. Silica gel chromatography, EtOAc/heptane 20-80% to give title compound (mix of regioisomers, 150mg, 0.470mmol). 1H NMR (400 MHz, MeOD) 6 7.54 (s, 0.6H), 7.46 (s, 0.4H), 7.36 — 6.99 (m, 5H), 5.31 (s, 0.8H), 5.21 (s, 1.2H), 4.44 (t, J = 6.9 Hz, 1H), 2.21 (2s, 3H), 1.54 (2dt, 3H), 1.17 (s, 9H).
MS 320.2 m/z (M+H) Intermediate 69: (S)(1-benzylmethyl-1H-pyrazolyl)ethanamine hydrochloride NEE/K Cf N’ (R)—N-((S)—1-(1-benzylmethyl-1H-pyrazolyl)ethyl)methylpropanesulfinamide was dissolved in dioxane (5ml) and 4N HCI in dioxane (1.2ml, 10eq.) was added. Stirred 1H at room termperature. The solvents were removed and co-vapped twice with CH2C|2.
Some t-butyl ed by NMR. itted to on conditions and work-up to give title compound. 1H NMR mixture of regioisomers (400 MHz, MeOD) 5 8.00 (s, 0.7H), 7.80 (s, 0.3H), 7.52 — 6.96 (m, 5H), 5.40 (s, 0.6H), 5.36 (s, 1.4H), 4.47 (q, J = 6.9 Hz, 1H), 2.34 (s, 2.1H), 2.32 (s, 0.9H), 1.62 (2d, J = 6.9 Hz, 3H).
MS 216.3 m/z (M+H) The Intermediates in Table 4h were prepared by methods substantially similar to those described for the preparation of Intermediates 56 through 69.
Table 4h.
Intermediate 70 Intermediate 71 Intermediate 72 Intermediate 73 ediate 74 Intermediate 75 Intermediate 79 Intermediate 80 Intermediate 81 Intermediate 82 Intermediate 83 Intermediate 84 I Intermediate 86 Intermediate 87 Intermediate 88 Intermediate 91 Intermediate 92 Intermediate 93 Amp/K2 mfifojv ediate 94 Intermediate 95 Intermediate 96 NHBoc Intermediate 97 ediate 98 Intermediate 99 2012/055133 Intermediate 100 ediate 101 Intermediate 102 MHZ MM Intermediate 103 Intermediate 104 Intermediate 105 Intermediate 106 Intermediate 107 Intermediate 108 _ntermediate109 Intermediate 110 _termediate111 _ntermediate112 Intermediate 113 _termediate114 Intermediate 115 Intermediate 116 Intermediate 117 Intermediate 119 Intermediate 120 nItermediate 121 Intermediate 122 Intermediate 123 Table 4i. al name, NMR al shifts and LCMS signal for each intermediate listed in Table 4h.
Intermediate: Name H NMR 400 MHz 8 ppm _CMS 70: (S)(3-fluoro—4-((3,3,4- M—Sm/z trimethylpiperazin 280.2 (M + I meth I phen I ethanamine 71: (S)-tert-butyl 1-(4-bromo (CDCI3) 7.51— 7.45 (m, 1H), II\_|/IS m/z fluorophenyl)ethylcarbamate 7.07 (dd, J = 9.8, 2.0 Hz, 1H), 317.9 (M + 6.98 (dd, J = 8.4, 2.1 Hz, 1H), H). 4.67 br s, 1H 1.41 ,, br s, 12H 72: (S)-tert-buty| 1-(3-quoro((4- (CDCI3) 7.28 (t, J = 7.7 Hz, 1H), MS m/z methylpiperazin 7.01 (dd, J = 7.7, 1.8 Hz, 1H), 353.2 (M + H) yl)methyl)phenyl)ethylcarbamate 6.94 (dd, J = 10.8, 1.9 Hz, 1H), 4.86 (br s, 1H), 4.74 (br s, 1H), 3.54 (s, 2H), 2.67 — 2.29 (m, 8H), 2.25 (s, 3H), 1.51 — 1.26 73: S 3-fluor04- —— WO 46136 m—-|meth| phen | ethanamine 74: (S)-benzy| 4-(4-(1-(tert- (CDCI3) 7.43 — 7.19 (m, 9H), MS m/z butoxycarbonylamino) 5.12 (s, 2H), 4.78 (br s, 2H), 454.3 (M + H) ethyl)benzyl)piperazine—1- 3.95— 3.20 (m, 6H), 2.43 (br s, carbox late 1.43 brs, 12H 75: (S)-benzy| 4-(4-(1- MS m/z aminoethy|)benzy|)piperazine—1- 354.3 (M + H) carbox late 76: (1S)—1-(4-((3,5- MS m/z | meth | phen | ethanamine 77: (S)-tert-buty| 1-(4-((4-methy|-1,4- (CDCI3) 7.31 — 7.20 (m, 4H), MS m/z diazepan 4.78 (s, 1H), 3.61 (s, 2H), 2.81- 349.4 (M + H) y|)methy|)phenyl)ethy|carbamate 2. 69-(,m 8H), 2.44 (s, 3H), 1. 94 ,1 .43 brs,12H 1- | meth | phen | ethanamine 248. 1 M + H 79: (S)(4-((4-tert—buty|piperazin—MS m/z | meth | ohen | ethanamine 2.762 M + H 80: (S)(4-((3,3,4- MS m/z trimethylpiperazin 262.2 (M + H) | meth | phen | ethanamine 81: (S)-tert-buty| 1-(4-((4- ) 7.28-7.22 (m, 4H), 4.78 MS m/z 363.4 isopropylpiperazin (s, 1H), 3.49 (s, 2H), 2.88 — y|)methy|)phenyl)ethy|carbamate 2.22 (m, 9H), 1.42 (br s, 12H), 1.05 d, J = 6.5 Hz, 6H | meth | phen | ethanamine 262.2 M + H 83: (1S)—1-(4-((3,4- MS m/z dimethylpiperazin _ 248.2 (M + H) | meth | phen | ethanamine 84: (S)-tert—buty| (4,4- MS m/z difluoropiperidin 356.2 (M + H) | meth | phen | eth Icarbamate | meth | phen | ethanamine 255.2 M + H 86: (S)—tert—buty| 1-(3-quoro—4-(4- ) 8.01 (t, J = 8.1 Hz, 1H), MS m/z (2,2,2-trifluoroethoxy) 7.16 (d, J = 7.9, 1H), 7.04 (d, J 463.3 (M + H) exylcarbamoyl) = 13.2, 1H), 6.67 -6.63(m, 1H), phenyl)ethy|carbamate 4.96 (br s, 1H), 4.76 (br s, 1H), 4.06 (br s, 1H), 3.85-3.77 (m, 2H), 3.64 (br s, 1H), 1.92 — 1.74 (m, 4H), 1.73 — 1.59 (m, 4H), 1.40 br s, 12H 87: (S)(1-aminoethy|)—2-f|uoro—N- MS m/z (4-(2,2,2- 363.2 (M + H) trifluoroethox c clohex | benzamide 88: (S)-tert—buty| 1-(3-fluoro—4-(4- (CDCI3) 8.04 (t, J = 8.1 Hz, 1H), hydroxy 7.19 (d, J = 8.3, 1H), 7.05 (dd, J 395.1 (M + H) methylcyclohexylcarbamoyl) = 13.2, 1.7 Hz, 1H), 6.65 (br dd, phenyl)ethy|carbamate J = 12.1, 6.6 Hz, 2H), 4.84 (br s, 1H), 4.77 (br s, 1H), 4.17 — 4.06 m, 1H ,2.09 —2.00 m, 2H), 1.61-1.59 (m, 4H), 1.55- 1.47 (m, 2H), 1.42 (br s, 12H), 89: (1-aminoethy|)—2-f|uoro—N- MS m/z (4-hydroxy—4- 295.2 (M + H) 90: tert-butyl (1S)—1-(3-f|uoro—4- MS m/z ((hexahydropyrrolo[1,2-a]pyrazin- 376.1 (M - H) 91: (1S)—1-(3-f|uoro—4- MS m/z ((hexahydropyrrolo[1,2-a]pyrazin- 278.1 (M + H) MS m/z 260.2 M + H 93: tert-butyl (1S)—1-(4-((dihydro—1H- (CDCI3) 7.30 — 7.20 (m, 4H), pyrido[1,2-a]pyrazin- 4.78 (s, 2H), 3.46 (s, 2H), 2.89 372.4 (M - H) 2(6H,7H,8H,9H,9aH)— — 2.61 (m, 4H), 2.39 — 2.21 (m, y|)methy|)phenyl)ethy|carbamate 2H), 2.10 — 1.93 (m, 2H), 1.86 (t, J = 10.7 Hz, 1H), 1.79 — 1.68 (m, 1H), 1.62 (br s, 2H), 1.43 94: (1S)—1-(4-((dihydro—1H- MS m/z pyrido[1,2-a]pyrazin- 274.2 (M + H) 2(6H,7H,8H,9H,9aH)— | meth | phen | ethanamine 95: tert-butyl (1S)—1-(4-((3-methy|— MS m/z 3,8-diazabicyclo[3.2.1]octan 361.3 (M + H) | meth | phen | eth Icarbamate 96: (1S)—1-(4-((3-methy|—3,8- MS m/z diazabicyc|o[3.2.1]octan 260.2 (M + H) | meth | phen | ethanamine 97: tert-butyl (1S)—1-(4-((8-methy|— (CDCI3) 7.28 — 7.19 (m, 4H), MS m/z azabicyclo[3.2.1]octan 4.77 (br s, 2H), 3.44 (s,2H), 360.6 (M + H) y|)methy|)phenyl)ethy|carbamate 3.03 (br s, 2H), 2.55 (dd, J = .8, 2.9 Hz, 2H), 2.29 (d, J = .3 Hz, 2H), 2.25 (s, 3H), 1.93 — 1.78 (m, 4H), 1.64 (br s, 1H), 1.43 br s, 12H 98: (1S)—1-(4-((8-methy|—3,8- MS m/z diazabicyc|o[3.2.1]octan 260.2 (M + | meth | phen | ethanamine H . 99: utyl (1S)—1-(4- (CDCI3) 7.30 — 7.21 (m, 4H), MS m/z ((hexahydropyrrolo[1,2-a]pyrazin- 4.78 (br s, 1H), 3.61 — 3.44 (m, 361.3 (M + H) 2(1H)— 2H), 3.05 (td, J = 8.6, 1.9 Hz, y|)methy|)phenyl)ethy|carbamate 1H), 3.00 — 2.93 (m, 2H), 2.86 — 2.76 (m, 1H), 2.33 — 2.19 (m, 2H), 2.17 — 2.00 (m, 2H), 1.87 — 1.65 m, 4H , 1.43 brs,12H 100: (1S)—1-(4- MS m/z hydropyrrolo[1,2-a]pyrazin- 260.2 (M + H) 2 1H - | meth | phen | ethanamine c clohex I-eth lamine 237.4 M + H)+; RT.: 1.08 min. 102: rt-buty| 1-(4-((4- (CDCI3) 7.28 — 7.20 (m, 4H), MS m/z 361.8 (dimethylamino)piperidin 4.79 (br s, 2H), 3.46 (s, 2H), (M + H) y|)methy|)phenyl)ethy|carbamate 2.91 (br d, J = 12.1 Hz, 2H), 2.26 (s, 6H), .09 (m, 1H), 1.94 (td, J = 11.8, 2.4 Hz, 2H), 1.85 (br s, 1H), 1.81 — 1.71 (m, 2H), 1.53 (td, J = 12.1, 3.7 Hz, 1.44—1.42 , m, 12H N,N-dimeth Ipiperidinamine 262.1 M + H 104: tert—butyl (1S)—1-(4-((3,5- (CD30D) 7.29 (s, 4 H), 4.68 (br MS m/z 348.3 dimethylpiperazin s, 1 H), 3.52 (s, 2 H), 2.96 - (M + H) y|)methy|)phenyl)ethy|carbamate 2.88 (m, 2 H), 2.82 - 2.79 (m, 2 H), 1.69 (t, J =11 Hz,2 H), 1.44 (br s, 9 H), 1.40 (d, J = 7.1 Hz, 3 H), 1.06 (d, J = 6.5 Hz, 6 105: (S)-tert-buty| 1-(4-((3,3,4- (CD30D) 5 7.35 - 7.25 (m, 4 H), MS m/z 362.3 trimethylpiperazin 4.67 (br s, 1 H), 4.59 (s, 1 H), (M + H) y|)methy|)phenyl)ethy|carbamate 3.45 (s, 2 H), 3.31 (s, 1 H), 2.62 (br s, 2 H), 2.51 (br s, 1 H), 2.24 (s, 3 H), 2.18 (br s, 1 H), 1.43 (br s, 9 H), 1.40 (d, J = 7.1 106: ((S)-tert-buty| 1-(4-((4- (CDCI3) 8 7.21 - 7.16 (m, 4 H), MS m/z 359.8 cyclopropylpiperazin 5.23 (s, 1 H), 4.72 (br s, 1 H), (M + H) y|)methy|)phenyl)ethy|carbamate 3.42 (s, 2 H), 2.58 (br s, 4 H), 2.38 (br s, 4 H), 1.57 - 1.51 (m, 1 H), 1.41 - 1.30 (br m, 12 H), 0.39 - 0.33 m, 4 H ' 107: rt-buty| 1-(4-((tert- (CDCI3) 7.32 (d, J = 8.0 Hz, MS m/z 308.2 butylamino)methyl)phenyl) 1H), 7.25 (d, J = 8.2 Hz, 1H), (M + H)+ ethylcarbamate 4.77 (s, 1H), 3.72 (s, 1H), 1.43 d, J = 5.4 Hz, 6H 2-meth Ipropanamine M + H + 109: (S)-tert-buty| 1-(4-(tert- (CDCI3) 7.71 — 7.62 (m, 2H), MS m/z 321.2 butylcarbamoyl)pheny|)ethyl 7.33 (d, J = 8.1 Hz, 2H), 5.90 (M + H)+ carbamate (3, 1H), 4.80 (br s, 2H), 1.46- but mide h drochloride M + H + 111: (S)-tert-buty| 1-(4- (CDCI3) 7.71 (dd, J = 8.3, 1.8 MS m/z 347.2 (cyclohexylcarbamoyl)pheny|)ethy| Hz, 2H), 7.35 (d, J = 7.8 Hz, (M + H)+ carbamate 2H), 5.91 (d, J = 8.3 Hz, 1H), 4.94 — 4.59 (m, 2H), 3.97 (ddt, J = 10.8, 6.5, 2.9 Hz, 1H), 2.02 (dt, J = 12.6, 3.7 Hz, 2H), 1.75 (dp, J = 11.8, 3.9 Hz, 2H), 1.66 — 1.56 (m, 3H), 1.49 — 1.30 (m, 112: s 1-aminoeth I -N- — MSm/z247.3 WO 46136 c clohex Ibenzamide h drochloride 113: (S)-tert-buty| 1-(4- (CDCI3) 7.90 — 7.83 (m, 2H), MS m/z 340.6 (phenylcarbamoyl)phenyl)ethy| 7.81 — 7.62 (m, 3H), 7.49 — (M + H) + carbamate 7.36 (m, 4H), 7.18 (td, J = 7.4, 1.2 Hz, 1H), 4.87 (br s, 2H), 114: (S)(1-aminoethy|)—N- MS m/z 241.2 phen Ibenzamide h drochloride M + H + 115: (S)-tert-buty| piperidine—1- (CDCI3) 7.33 (q, J = 8.3 Hz, MS m/z 333.2 carbonyl)pheny|)ethylcarbamate 4H), 4.80 (br s, 2H), 3.70 (br s, (M + H) + 2H), 3.47 — 3.22 (m, 2H), 1.70- 1.63 (m, 4H), 1.53 — 1.28 (m, 116: (S)-(4-(1-aminoethy|)pheny|) MS m/z 233.2 (piperidiny|)methanone (M + H) + h drochloride 117: (S)-tert-buty| 1-(4-(4- (CDCI3) 7.35 (q, J = 8.2 Hz, MS m/z 348.2 methylpiperazine—1- 4H), 4.81 (br s, 1H), 3.79 (brs, (M + H) + carbonyl)pheny|)ethylcarbamate 2H), 3.45 (br s, 2H), 2.50 - 2.32 (m,7H), 1.81 (s, 1H), 1.51 — 118: (S)-(4-(1-aminoethy|)pheny|)(4- MS m/z 248.2 methylpiperaziny|)methanone (M + H) + h drochloride 119: (S)-tert-buty| 1-(4-(piperidin (CDCI3) 7.27 (q, J = 7.9 Hz, MS m/z 319.0 y|methy|)pheny|)ethylcarbamate 4H), 4.80 (br s, 2H), 3.49 (s, (M + H) + 2H), 2.60 — 2.28 (m, 4H), 1.80 (p, J = 5.5 Hz, 4H), 1.52 — 1.31 120: (4-(piperidin MS m/z219.1 Imeth | phen | ethanamine M + H + 121: (S)-tert-buty| 1-(4- (CDCI3) 7.48 — 7.10 (m, 4H), MS m/z 321.2 (morpholinomethy|)pheny|)ethy| 4.82 (d, J = 25.7 Hz, 2H), 3.80 (M + H) + carbamate — 3.62 (m, 3H), 3.48 (s, 2H), 2.61 — 2.24 (m, 3H), 1.44 (m, 122: (4-(morpholinomethy|) MS m/z 220.9 phen | ethanamine M + H + 123: (S)-tert-buty| 1-(4-((4- (CDCI3) 7.39 — 7.15 (m, 7H), MS m/z 321.2 methylpiperazin 4.79 (br s, 2H), 3.51 (s, 2H), (M + H) + | meth | ohen leth Icarbamate 124: (S)(4-((4-methy|piperazin MS m/z 234.2 | meth | phen | ethanamine M + H + 125: 4-((S)Amino—ethy|)— LC-MS (M+H) piperidine—1-carboxylic acid benzyl =263.1 RT.: ester Intermediate 126: (S)-(4-(1-aminoethyl)f|uorophenyl)methanol F NH2 To a cooled (0 °C) suspension of (S)-methyl 4-(1-aminoethyl)f|uorobenzoate hydrochloride (0.109 g, 0.468 mmol) in THF (15 mL) was added a solution of LAH in THF (2.0 M, 1.05 mL, 2.10 mmol, 4.49 equiv) and the resulting mixture was stirred at 0 °C for 2 h 20 min and at room temperature for 2 1/2 h. The reaction mixture was quenched by addition of a mixture of Na2804 decahydrate and Celite (1:1 by ) until gas ion ceased. The on mixture was filtered, washed with EtOAc. The filtrate was concentrated and used for the next reaction without purification. 1H NMR (400 MHz, CD30D) 6 7.43 (t, J = 7.7 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 7.08 (d, J =12 Hz, 1 H), 4.60 (s, 2 H), 4.32 (q, J = 6.6 Hz, 1 H), 1.42 - 1.40 (m, 3 H).
Intermediate 127: 4-((S)(4-((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzaldehyde HNJN\\%NE\NJZ \“L/0 o \\ A solution of (S)(2-((S)—1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone (285 mg, 0.8 mmol) and manganese dioxide (2.78 g, 32 mmol, 40 equiv) in DCM (16 mL) was stirred at room temperature for 30 min. The solution was filtered through a pad of celite and washed with DCM. The filtrated was concentrated and used to next step without further cation.
Intermediate 128: tert-butyl 4-(4-((S)—1-(4-((S)isopropyloxooxazolidin yl)pyrimidinylamino)ethyl)benzyl)-2,2-dimethylpiperazinecarboxylate A solution of 4-((S)(4-((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzaldehyde (71 mg, 0.2 mmol) and tert-butyl 2,2-dimethylpiperazine carboxylate (47.1 mg, 0.22 mmol) in MeOH (4 mL) was added acetic acid (14.4 mg, 0.24 mmol) and 5-Ethylmethylpyridine borane complex (27 mg, 0.2 mmol, sigma aldrich).
The solution was d at 50 °C for 4 h then 5 drops of water was added. The solution was stirred at room temperature for another 2 h then diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 10 mL). ed cs were dried over Na2804, filtered and concentrated. The crude material was ed through Silica gel column chromatography (MeOH/EtOAc 0 to 10%) to give tert-butyl 4-(4-((S)(4-((S)isopropyloxooxazolidin- 3-yl)pyrimidinylamino)ethyl)benzyl)-2,2-dimethylpiperazinecarboxylate as a white solid (80 mg, 72.4% yield). 1H NMR (400 MHz, CDCI3) 5 8.18 (br s, 1H), 7.44 (d, J = 5.7 Hz, 1H), 7.24-7.29 (m, 4H), 5.46 (br s, 1H), 5.03 (br s, 1H), 4.59-4.63 (m, 1H), 4.29 (t, J = 8.7 Hz, 1H), 4.22 (dd, J = 9.1, 3.1 Hz, 1H), 3.44 (br s, 4H), 2.40 (s, 2H), 2.16 (s, 2H), 1.54 (d, J = 6.9 Hz, 3H), 1.45 (s, 9H), 1.36 (s, 6H), 0.80 — 0.57 (m, 6H); MS m/z 252.1 (M + H).
Intermediate 129: tert-butyl 1-(4-((S)—1-(4-((S)isopropyloxooxazolidin yl)pyrimidinylamino)ethyl)benzyl)methy|piperidinylcarbamate Prepared by a method similar to that described for the preparation of Intermediate 128. 1H NMR (400 MHz, CDCI3) 8.17 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.26 (br s, 4H), 5.40 (br s, 1H), 5.02 (br s, 1H), 4.60 (dt, J = 8.2, 3.1 Hz, 1H), 4.34 — 4.19 (m, 3H), 3.47 (br s, 2H), 2.54 (br s, 2H), 2.26 (br s, 2H), 1.95 (br s, 3H), 1.60 (br s, 2H), 1.53 (d, J = 6.9 Hz, 3H), 1.43 (s, 9H), 1.33 (s, 3H), 0.69 (br s, 3H), 0.63 (br s, 3H). MS m/z 553.6 (M + H).
Intermediate 130: tert-butyl (S)(4-bromophenyl)ethyl(4-((S)—4-isopropyl oxooxazolidinyl)pyrimidinyl)carbamate >LALNN1$LAZ To a solution of (S)(2-((S)—1-(4-bromophenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone (1.62 g, 4 mmol) in THF (20 mL) was added t—butyl dicarbonate (1.31 g, 6 mmol), DMAP (49 mg, 0.4 mmol) and DIPEA (1.40 mL, 8 mmol).
The solution was stirred at 50 °C for 7 days then concentrated under reduced pressure.
The residue was diluted with EtOAc (40 mL) and washed with water and brine. The organic layer was dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 80%) provided utyl (4- bromophenyl)ethyl(4-((S)—4-isopropyloxooxazolidinyl)pyrimidinyl)carbamate as a white solid (1.03 g, 50.9% yield). 1H NMR (400 MHz, CDCI3) 6 8.57 (d, J = 5.8 Hz, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.44 — 7.39 (m, 2H), 7.33 — 7.28 (m, 2H), 5.63 (q, J = 7.2 Hz, 1H), 4.63 (dt, J = 8.0, 3.3 Hz, 1H), 4.39 — 4.26 (m, 2H), 2.47-2.39 (m, 1H), 1.66 (d, J = 7.1 Hz, 3H), 1.30 (s, 9H), 0.84 (d, J = 7.0, 3H),0.83 (d, J = 7.0, 3H); MS m/z 507.0 (M + H).
Intermediate 131: tert-butyl 4-((S)isopropyloxooxazolidinyl)pyrimidinyl((S)—1- (4-(1-methyl-1H-pyrazolyl)phenyl)ethyl)carbamate >LOALNILTALNAZ 7©*"W In a 5 mL microwave vial a solution of tert-butyl (4-bromophenyl)ethyl(4-((S)—4- isopropyloxooxazolidinyl)pyrimidinyl)carbamate (101 mg, 0.2 mmol), 1-methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole (50 mg, 0.24 mmol), Sodium bicarbonate (0.2 mL, 0.4 mmol, 2 M aqueous solution) in Dioxane (2 mL) was bubbled N2 for 3 min then CI2Pd(dppf)CH2C|2 (16 mg, 0.02 mmol) was added. The capped tube was heated to 100°C for 16 h. After cooling the reaction mixture was d with EtOAc (10 mL) and washed with water (10 mL). After separation, the s phase was extracted with EtOAc (3 x 10 mL). Combined organics were dried over Na2804, filtered and concentrated. The crude material was ed through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (50 mg, 49.3% yield). 1H NMR (400 MHz, CDCI3) 6 8.57 (d, J = 5.7 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.39 (s, 4H), 5.71 (q, J = 7.0 Hz, 1H), 4.65 (dt, J = 8.1, 3.2 Hz, 1H), 4.36 — 4.24 (m, 2H), 3.94 (s, 3H), 2.50-2.42 (m, 1H), 1.71 (d, J = 7.0 Hz, 3H), 1.29 (s, 9H), 0.82 (d, J = 7.0 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H); MS m/z 507.1 (M + H).
Intermediate 132: utyl (S)(4-(cyclohexanecarboxamido)phenyl)ethyl(4-((S) isopropyloxooxazolidinyl)pyrimidinyl)carbamate >KOJKNJsN0 N1 0 OiND/k \{L/ In a 5 ml microwave reaction vial was added tert-butyl (S)(4-bromophenyl)ethyl(4-((S)- 4-isopropyloxooxazolidinyl)pyrimidinyl)carbamate (101 mg, 0.2 mmol), cyclohexanecarboxamide (30 mg, 0.24 mol), cesium carbonate (91 mg, 0.28 mmol), XANTPHOS (7 mg, 0.012 mmol, strem chemicals), and Pd2(dba)3 (4 mg, 0.02 mmol).
The vial was sealed, evacuated and purged with dry nitrogen three times before adding dioxane (1.6 mL). The reaction e was heated to 100°C for 16 hours in an oil bath.
After cooling the reaction was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 10 mL).
Combined cs were dried over Na2804, filtered and concentrated. The crude material was purified through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (65 mg, 58.9% yield). 1H NMR (400 MHz, CDCI3) 6 8.55 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 5.8 Hz, 1H), 7.48 — 7.43 (m, 2H), 7.38 — 7.32 (m, 2H), 7.13 (br s, 1H), 5.66 (q, J = 7.1 Hz, 1H), 4.64 (dt, J = 8.2, 3.2 Hz, 1H), 4.38 — 4.26 (m, 2H), 2.51 — 2.43 (m, 1H), 2.20 (tt, J = 11.8, 3.5 Hz, 1H), 1.95 (d, J = 13.2, 2H), 1.87 — 1.81 (m, 2H), 1.71— 1.68 (m, 4H), 1.60 — 1.47 (m, 2H), 1.33-1.25(m, 12H), 0.85 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H); MS m/z 552.1 (M + Intermediate 133: (S)-methyl 2-((4-((S)—4-isopropyloxooxazolidinyl)pyrimidin no)propanoate i:LNJZ :YHLW‘U To a solution of (S)-methyl 2-aminopropanoate (270 mg, 2.0 mmol, 1.2 n 10 ml of DMSO) and (S)(2-chloropyrimidinyl)isopropyloxazolidinone (430 mg, 1.8 mmol, 1.0 equv.) was added DIPEA (805 mg, 6.23 mmol, 3.5 equiv), and the reaction mixture was heated at 110 °C for 120 min. The reaction mixture was poured into water (40ml) and ted with EtOAc (2x30 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (ethyl acetate in heptane 10 to 80%) to provide (S)-methy| ((S)isopropy| oxooxazolidinyl)pyrimidinyl)amino)propanoate (260 mg, white solid) in 47.4% yield.
LCMS m/z 309.1 (M + H)+ RT=1.53 min.
Intermediate 134: (S)((4-((S)isopropyloxooxazolidinyl)pyrimidin y|)amino)propanehydrazide To a on of (S)-methyl 2-((4-((S)—4-isopropyloxooxazolidinyl)pyrimidin y|)amino)propanoate (120 mg, 0.39 mmol in 5 ml of MeOH) was added 99% hydrazine hydrate, the reaction solution was stirred at room temperature overnight (24 hours), the solvent was removed to yield the desired product (99 mg) in 78% yield, and was used for next step without purification. LCMS m/z 309.1 (M + H)+ RT=1.25 min.
Intermediate 135: (S)—tert-butyl razinyloxopropanyl)carbamate A solution of hydrazine (234 mg, 7.31 mmol, 1.5 equv. in 8 ml of THF) was added to (8)- methyl 2-(tert—butoxycarbonylamino)propanoate (1000 mg, 4.88 mmol, 1.0 equv.), it was stirred in a sealed tube and ed (72°C) overnight (18 hours), the solvent was removed to yield the desired product (880 mg, white solid) in 84% yield.
Intermediate 136: (S)-tert-butyl (1-(2-benzoylhydrazinyl)—1-oxopropany|)carbamate 6“\ij/HYOor To a solution of (S)-tert-butyl (1-hydrazinyloxopropany|)carbamate (293 mg, 1.44 mmol, 1.0 equv. in 3 ml of DCM) was added benzoyl fluoride (179 mg, 1.44 mmol in 2 ml of DCM), the reaction solution was stirred at room temperature for 50 min., the solvent was removed to yield the desired product. 1H NMR (400 MHz, CDCI3) 6 7.89 — 7.78 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 5.32 (b, 1H), 4.45 (b, 1H), 1.46 (s, 9H).
Intermediate 137: (S)-tert-butyl phenyl-1,3,4-thiadiazolyl)ethyl)carbamate @4866 To a solution of (S)-tert-butyl benzoylhydrazinyl)—1-oxopropanyl)carbamate (155 mg, 0.5 mmol, 1.0 equv. in 5 ml of THF) was added Lawesson's reagent (36.4 mg, 0.5 mmol, 1.0 equv.) the reaction mixture was stirred at reflux for 3 hours, the reaction mixture was filtered and the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) to provide (S)—tert-buty| (1- nyl-1,3,4-thiadiazolyl)ethyl)carbamate (114.6 mg, white solid) in 70.7% yield. 1H NMR (400 MHz, CDZCIZ) 6 7.94 — 7.72 (m, 2H), 7.52 — 7.26 (m, 3H), 5.59 (b, 1H), 5.11 (b, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.34 (s, 9H).
WO 46136 Intermediate 138: (S)(5-phenyl-1,3,4-thiadiazolyl)ethanamine N--N / \ NI"2 To a solution of (S)-tert-butyl (1-(5-phenyl-1,3,4-thiadiazolyl)ethyl)carbamate (110 mg, 0.4 mmol, in 5 ml of DCM )was added 1 ml of TFA, the reaction mixture was stirred at room temperature for 3 hours, the solvent was removed to yield the desired product (52 mg) in 66.8% yield. LCMS m/z 206.0 (M + H)+ RT=0.97min.
Intermediate 139: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidinyl)ethanone A cloudy solution of 1-(5-bromopyrimidinyl)ethanone (300 mg, 1.49 mmol), 3- (trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K3PO4 (950 mg, 4.48 mmol), DavePhos ligand [2-dicyclohexylphosphino—2’-(N,N-dimethylamino)biphenyl] (59 mg, 0.15 mmol), and Pd(OAc)2 (17 mg, 0.075 mmol) in 6 mL toluene was heated at 100°C for 1 h. The e was cooled to room temperature, and filtered through Celite. Filter cake was rinsed with 30 mL EtOAc. The filtrate was poured into 20 mL water. Layers were separated, and the aqueous was further extracted with EtOAc (20 mL). Combined organics were washed with water (20mL) and brine (20mL), dried over Na2804, filtered and concentrated directly onto silica gel. Column chromatography (10 - 100% EtOAc/heptane) gave 0.26 g 1-(5-(3-(trifluoromethyl)phenyl)pyrimidinyl)ethanone (V) as tan solid. MS m/z 267.1 (M + H)+. 1H NMR (400 MHz, CDCI3) 5 9.16 (s, 2H), 7.93 — 7.69 (m, 4H), 2.87 (s, 3H).
The Following intermediates were prepared using a method similar to that described for the preparation of Intermediate 139. Using Anal. RP-HPLC Column = il C8 Column, 3.0 pm, 3.0 x 30 mm. Column ature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; % to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) Intermediate 140: 1-(5-(3,4-dichIorophenyl)pyrimidiny|)ethanone.
Anal. RP-HPLC tR = 1.17 min. MS m/Z 266.9 (M + H)+.
Intermediate 141: 3-f|uoro—2-methylphenyl)pyrimidiny|)ethanone.
Anal. RP-HPLC tR = 1.07 min. MS m/z 231.1 (M + H)+.
Intermediate 142: 1-(5-(4-f|uoro—2-methylphenyl)pyrimidiny|)ethanone.
Anal. RP-HPLC tR = 1.18 min.MS m/z 231.1 (M + H)+.
Intermediate 143: 1-(5-(5-f|uoro—2-methylphenyl)pyrimidiny|)ethanone Anal. RP-HPLC tR = 1.16 min. MS m/z 231.2 (M + H)+.
Intermediate 144: 1-(5-(4-f|uoro—3-methylphenyl)pyrimidinyl)ethanone 1H NMR (400 MHz, 00013) 6 9.09 (s, 2H), 7.52 — 7.41 (m, 2H), 7.24 — 7.16 (m, 1H), 2.85 (s, 3H), 2.41 (d, J = 2.0 Hz, 3H). Anal. RP-HPLC tR = 1.20 min.MS m/z 231.0 (M + H)+. ediate 145: 1-(5-(2,3-dichIorophenyl)pyrimidin-Z-yl)ethanone I NVK Anal. RP-HPLC tR = 1.15 min. MS m/Z 267.9 (M + H)+.
Intermediate 146: 1-(5-(4-f|uoro—3-methylphenyl)pyridinyl)ethanone. 1H NMR (400 MHZ, CDCI3) 6 8.88 (dd, J = 2.3, 0.8 Hz, 1H), 8.13 (dd, J = 8.1, 0.8 HZ, 1H), 7.98 (dd, J = 8.1, 2.3 Hz, 1H), 7.50 — 7.39 (m, 2H), 7.21 — 7.12 (m, 1H), 2.78 (S, 3H), 2.42 — 2.36 (m, 3H). Anal. RP-HPLC tR = 1.40 min. MS m/z 230.8 (M + H)+.
Intermediate 147: 1-(5-(3-(trifluoromethyl)phenyl)pyrimidinyl)ethanamine 1-(5-(3-(Trifluoromethyl)phenyl)pyrimidinyl)ethanone (260 mg, 0.977 mmol), NH4OAc (1.13 g, 14.6 mmol), and NaBH3CN (245 mg, 3.91 mmol) were taken up in 8 mL 200 proof EtOH, and heated at 120°C for 5 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water + 25 mL EtOAc. 6N NaOH was added until aqueous pH was ~10. ted layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2804. Filtered and concentrated with reduced pressure to give 262 mg crude yellow oil, which was carried forward without r purification. Anal.
RP-HPLC tR = 0.90 min. (Column = il C8 Column, 3.0 pm, 3.0 x 30 mm. Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN.
Flow Rate =2 mL/min. nt =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 268.1 (M + H)+.
The Following intermediates were prepared using a method similar to that described for the preparation of Intermediate 147.
Intermediate 148: 1-(5-(3,4-dichlorophenyl)pyrimidinyl)ethanamine.
| N% Anal. RP-HPLC tR = 1.09 min (Gradient: 2 to 98% B in 1.7 min - flow 1 mL/min. Eluent A: Water + 3.75 mM NH4Ac + 2% ACN. Column: Acquity CSH 1.7um 2.1x50mm - 50°C.) MS m/z 268.4 (M + H)+.
Intermediate 149: 1-(5-(3-f|uoromethylphenyl)pyrimidinyl)ethanamine.
Anal. RP-HPLC tR = 0.99 min. (Gradient: 2 to 98% B in 1.7 min - flow 1 mL/min. Eluent A: Water + 3.75 mM NH4Ac + 2% ACN. Column: Acquity CSH 1.7um 2.1x50mm - 50°C.) MS m/z 232.4 (M + H)+.
Intermediate 150: 1-(5-(4-f|uoromethylphenyl)pyrimidinyl)ethanamine.
Anal. RP-HPLC tR = 0.87 min. (Column = il C8 Column, 3.0 um, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 231.0 (M)—.
Intermediate 151: 1-(5-(5-f|uoromethylphenyl)pyrimidinyl)ethanamine Anal. RP-HPLC tR = 0.79 min. (Column = lnertsil C8 Column, 3.0 um, 3.0 x 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM um formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 232.0 (M + H)+.
Intermediate 152: 1-(5-(4-fluoro—3-methylphenyl)pyrimidinyl)ethanamine I N% Anal. RP-HPLC tR = 0.81 min. (Column = Inertsil C8 Column, 3.0 um, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 231.9 (M + H)+. ediate 153: 1-(5-(2,3-dichlorophenyl)pyrimidinyl)ethanamine Anal. RP-HPLC tR = 1.01 min. (Column = Inertsil C8 Column, 3.0 um, 3.0 X 30 mm.
Column Temperature =50°C. s =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. nt =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 269.0 (M + H)+.
Intermediate 154: 1-(5-(4-fluoromethylphenyl)pyridinyl)ethanamine 2012/055133 Anal. RP-HPLC tR = 0.92 min. (Column = Inertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 230.9 (M + H)+.
Intermediate 155: 1-(5-(4-fluorophenoxy)pyrimidinyl)ethanamine Step 1: A solution of 1-(5-fluoropyrimidinyl)ethanone (700 mg, 5.0 mmol) and 4- fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was d with potassium ate (829 mg 6.0 mmol) and heated to 50°C for 3.5 h. The reaction mixture was poured into mL water, and extracted with EtOAc (2 x 20 mL). Organics were washed with 20 mL each water, brine, and dried over NaZSO4. Mixture was filtered and concentrated on silica gel. Column chromatography (10 - 100% EtOAc/hept) gave 295 mg (25%) 4- fluorophenoxy)pyrimidinyl)ethanone as a white solid used directly in the following step.
MS m/z 233.2 (M + H)+. 1H NMR (400 MHz, CDCI3) 6 8.55 (s, 2H), 7.23 — 7.07 (m, 4H), 2.78 (s, 3H).
Step 2: 1-(5-(4-fluorophenoxy)pyrimidinyl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH3CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water + 25 mL EtOAc. 6N NaOH was added until aqueous pH was ~10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and trated with reduced pressure to give 275 mg crude tan oil, which was carried forward without further purification. Major product Anal. RP-HPLC tR = 1.26 min. (Column = il C8 Column, 3.0 pm, 3.0 x 30 mm. Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 234.1 (M + H)+.
The Following intermediates were prepared using methods r to those described for the preparation of Intermediate 155.
Intermediate 156: 1-(5-(2,4-difluorophenoxy)pyrimidinyl)ethanamine Anal. RP-HPLC tR = 0.81 min. n = lnertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 252.1 (M + H)+.
Intermediate 157: 1-(5-(5-bromopyridinyloxy)pyrimidinyl)ethanamine Anal. RP-HPLC tR = 1.29 min. (Column = lnertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium e, 2% ACN); B: ACN. Flow Rate =2 . Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 297.3 (M + H)+.
Intermediate 158: 1-(5-(3-chlorofluorophenoxy)pyrimidiny|)ethanamine Anal. RP-HPLC tR = 1.40 min. (Column = lnertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 268.0 (M + H)+.
Intermediate 159: 1-(5-(pyridinyloxy)pyrimidinyl)ethanamine Anal. RP-HPLC tR = 1.21 min. (Column = Inertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column ature =50°C. s =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 218.4 (M + H)+.
Intermediate 160: 1-(5-(5-(trifluoromethyl)pyridinyloxy)pyrimidinyl)ethanamine Anal. C tR = 1.16 min. (Column = Inertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column ature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 285.4 (M + H)+.
Intermediate 161: 4-(4-fluorophenoxy)pyrimidinecarbonitrile A solution of 4-chloropyrimidinecarbonitrile (0.63 g, 4.51 mmol) and 4-fluorophenol (0.51 g, 4.51 mmol) in 5 mL DMF was cooled to 0°C under N2 atmosphere. NaH (0.217 g of 60% suspension, 5.42 mmol) was slowly added. Bubbling exotherm observed.
Internal temp was kept below 5°C. After 15 minutes, cold bath was removed. The reaction mixture was allowed to warm to room temp and stir 1 h. The reaction mixture was diluted with water (40 mL) and extracted with (3 x 25 mL) EtOAc. The organic layer was washed with 40 mL each water, and brine. Dried over Na2804, and concentrated on silica gel in vacuo. Column tography (EtOAc/heptane 10 to 100% nt) gave 0.72 g (74%) of (4-fluorophenoxy)pyrimidinecarbonitrile as a crystalline white solid. Anal. RP-HPLC tR = 1.38 min, Gradient: 2 to 98% B in 1.7 min - flow 1 mL/min.
Eluent A: Water + 3.75 mM NH4Ac + 2% ACN. Column: Acquity CSH 1.7um 2.1x50mm - 50°C. MS m/z 216.1 (M + H)+.
Intermediate 162: 1-(4-(4-fluorophenoxy)pyrimidinyl)ethanone 4-(4-fluorophenoxy)pyrimidinecarbonitrile (450 mg, 2.09 mmol) was suspended in 12 mL anhydrous ether under N2 atmosphere. Vessel was cooled to 0° C. MeMgBr (3.1 mL of 1.0 M solution in butyl ether, 3.10 mmol) was added over 5 min. The yellow-green suspension was stirred 30 minutes, then quenched with 50 mL sat'd NH4C| solution.
Adjusted pH to ~6 with conc. HCl. The mixture was extracted with (2 x 40 mL) EtOAc.
Washed organics with 30 mL brine, and dried over Na2804. ed and concentrated on silica gel. Column chromatography (10 - 100% EtOAc in hept) gave 157 mg (32%) 1- (4-(4-fluorophenoxy)pyrimidinyl)ethanone as a yellow oil. Anal. RP-HPLC tR = 1.44 min. (Column = lnertsil C8 Column, 3.0 pm, 3.0 x 30 mm. Column Temperature =50°C.
Eluents =A: Water (5 mM um formate, 2% ACN); B: ACN. Flow Rate =2 mL/min.
Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 233.2 (M + H)+.
Intermediate 163: 1-(4-(4-fluorophenoxy)pyrimidinyl)ethanol 1-(4-(4-f|uorophenoxy)pyrimidinyl)ethanone (0.150 g 0.646 mmol) was taken up in 2.5 mL 4:1 MeOH:DCM, and cooled to 0°C. NaBH4 (49 mg 1.30 mmol) was added. g was observed. After 10 min, cold bath was removed, and the reaction was stirred 1 h. t was removed in vacuo. White residue was taken up in 10 mL water, and extracted with (2 x 10 mL) EtOAc. Washed organics with 10 mL brine. Dried over Na2804. Filtered and concentrated to give 143 mg (95%) 1-(4-(4- fluorophenoxy)pyrimidinyl)ethanol as a colorless oil. Anal. RP-HPLC tR = 1.38 min.
(Column = Inertsil C8 Column, 3.0 um, 3.0 x 30 mm. Column Temperature =50°C.
Eluents =A: Water (5 mM um formate, 2% ACN); B: ACN. Flow Rate =2 mL/min.
Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 235.1 (M + H)+.
Intermediate 164: 2-(1-azidoethyl)(4-f|uorophenoxy)pyrimidine Under N2 atmosphere, 1-(4-(4-f|uorophenoxy)pyrimidinyl)ethanol (140 mg, 0.598 mmol) was dissolved in 3 mL anhydrous DCM. Triethylamine (0.175 mL, 1.26 mmol) was added, and the e was cooled to 0° C. MsCI (0.070 mL, 0.897 mmol) was added, and the e was stirred 15 minutes. Maintaining 0°C, DCM solvent was removed under N2 stream. Residue was taken up in 2 mL dry DMF. NaN3 (78 mg, 1.19 mmol) added, and the reaction was stirred at rt for 24 h. Mixture was poured into 20 mL water, and extracted with 20 mL EtOAc. Organic layer was washed with 20 mL brine and dried over Na2804. Filtered and concentrated to give 120 mg (77%) 2-(1-azidoethyl)—4-(4- fluorophenoxy)pyrimidine as a yellow oil. 1H NMR (400 MHz, CDCI3) 6 8.49 (d, J = 5.7 Hz, 1H), 7.16 — 6.90 (m, 4H), 6.70 (d, J = 5.7 Hz, 1H), 4.34 (q, J = 6.9 Hz, 1H), 1.55 — 1.46 (m, 3H).
Intermediate 165: 1-(4-(4-fluorophenoxy)pyrimidinyl)ethanamine zidoethyl)(4-f|uorophenoxy)pyrimidine (120 mg, 0.463 mmol) was dissolved in 2 mL neat EtOH. 24.6 mg (0.023 mmol) of 10% ium on carbon catalyst was added.
With vigorous stirring, the reaction vial was evacuated and purged 3 times with H2. The reaction vessel was fitted with an H2 balloon and stirred for 2 h. The mixture was filtered through Celite and concentrated in vacuo to give 75 mg (69%) 1-(4-(4- fluorophenoxy)pyrimidinyl)ethanamine as a brown oil. 1H NMR (400 MHz, CDCI3) 6 8.45 (d, J = 5.7 Hz, 1H), 7.13 — 6.92 (m, 4H), 6.59 (d, J = 5.7 Hz, 1H), 4.00 (q, J = 6.8 Hz, 1H), 1.34 — 1.30 (m, 3H). Anal. RP-HPLC tR = 1.18 min. (Column = lnertsil C8 Column, 3.0 pm, 3.0 X 30 mm. Column ature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; % to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 234.2 (M + H)+.
The Following intermediates were prepared using methods similar to those described for the preparation of Intermediates 161 to 165.
Intermediate 166: 1-(5-(4-f|uorophenoxy)pyridinyl)ethanamine Fm N Anal. RP-HPLC tR = 0.91 min. (Column = lnertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column ature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 233.1 (M + H)+.
Intermediate 167: 1-(5-(4-f|uorophenoxy)pyrazinyl)ethanamine FOt3*O N Anal. RP-HPLC tR = 1.39 min. (Column = Inertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column Temperature =50°C. s =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 217.1 (Major fragment + H)+.
Intermediate 168: 1-(2-(4-fluorophenoxy)pyrimidinyl)ethanamine F0 WAOAN/ Anal. RP-HPLC tR = 1.20 min. (Column = Inertsil C8 Column, 3.0 pm, 3.0 X 30 mm.
Column Temperature =50°C. Eluents =A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate =2 mL/min. Gradient =0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1%B.) MS m/z 233.9 (M + H)+.
Intermediate 169: (S)lsopropyl[2-((S)—1-methyl-propynylamino)—pyrimidinyl]— oxazolidinone “9 ° /\fi)\N Tikjo To a on of compound (S)(2-Ch|oro-pyrimidinyl)isopropy|-oxazo|idinone (1.03 g in DMSO (12 mL) was added methyl-propynylamine HCl salt (450 , 4.3 mmol) mg, 4.3 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol). The on was heated to 110C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL) and brine (25 mL). The c layer was dried over Na2804, filtered and concentrated. The crude material was purified on silica gel column chromatography (EtOAc/Heptane 0 to 75%) provided (S)lsopropyl[2-((S)—1-methyl-prop ynylamino)—pyrimidinyl]—oxazolidinone (360 mg) in 31% yield.
LC-MS m/z : 275.1 (M - Boc)+; RT.: 1.33 min.
Intermediate 170: (S)—4,6-difluoro-N-(1-phenylethyl)pyrimidinamine HN N F (3)].
A solution of 2,4,6-trifluoropyrimidine (128.4 mg, 0.96 mmol) and isopropylethylamine (0.50 mL, 2.9 mmol, 3 equiv) in dioxane (5 mL) was cooled to 0 °C with an ice bath. After min, the ice bath was removed, and the reaction was allowed to warm to room temperature. After stirriing overnight, the reaction was concentrated to a light brown oil and ed by silica gel column chromatography (EtOAc/Heptane 0 to 100%) to provide (S)—4,6-difluoro-N-(1-phenylethyl)pyrimidinamine (151.2 mg, white solid) in 45% yield. 1H NMR (400 MHz, CD30D) 8 7.35 - 7.40 (m, 2H), 7.29 - 7.34 (m, 2H), 7.20 - 7.26 (m, 1H), 5.84 (s, 1H), 5.08 (q, J = 6.91 Hz, 1H), 1.52 (d, J = 7.04 Hz, 3H); LCMS m/z 236.1 (M + H)+, R 0.95 min.
Intermediate 171: (S)-4,6-difluoro—N-(1-(2-fluoro(trifluoromethyl)phenyl)ethyl) pyrimidinamine ediate 171 was prepared by a method similar to the one described for the preparation of ediate 170. 1H NMR (400 MHz, CD30D) 7.58 (t, J = 7.63 Hz, 1H), 7.34 - 7.48 (m, 2H), 5.84 (br. s., 1H), 5.35 (q, J = 6.91 Hz, 1H), 1.54 (d, J = 7.04 Hz, 3H).
MS m/z 321.9 (M + H)+, Rt 1.11 min.
Intermediate 172: tert-butyl 3-hydroxymethylbutanylcarbamate [Boc HN OH 2012/055133 Step 1: Preparation of tert-butyl 1-(methoxy(methyl)amino)methyloxopropan- 2-ylcarbamate 2-(tert-butoxycarbonylamino)methylpropanoic acid (6.62 g, 32.6 mmol), O,N- dimethylhydroxylamine hloride (3.50 g, 35.8 mmol), and HATU (14.86 g, 39.1 mmol) were combined in DMF (100 mL). To this solution was added Hunig'sBase (17.07 mL, 98 mmol). The reaction was stirred for overnight (17 hours). The reaction was then trated under vacuum and the e was diluted with EtOAc (300mL) and washed with water (2x80mL). The organic layer was washed with brine, dried (Na2804), and concentrated under reduced pressure. The residue was ed via silica gel flash chromatography (10-50 percent EtOAc-Hexanes) to afford the desired product as a white solid (6.36 g). LCMS m/z 247.2 (M + H)+, Rt 0.61 min.
Step 2: Preparation of utyl yloxobutanylcarbamate To a solution of tert—butyl 1-(methoxy(methyl)amino)—2-methyloxopropan ylcarbamate (4.26 g, 17.30 mmol) in THF (100 mL) at -70 °C was added drop wise methyl lithium (32.4 mL, 51.9 mmol). Cold bath was replaced with -40 oC bath and the reaction was d for 4 hours. Saturated NH4C| solution (10mL) was then added cautiously to quench the reaction. The reaction mixture was then d to warm to room temperature, and diluted with EtOAc (100mL) and water (50mL). The phases were separated and the aqueous layer was extracted with EtOAc (2x100mL). The combined organics were then dried (Na2804) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.36 g). LCMS m/z 224.2 (M + Na)+, Rt 0.7 min.
Step 3: Preparation of tert-butyl 3-hydroxymethylbutanylcarbamate To a solution of tert-butyl 2-methyloxobutanylcarbamate (2.36g, 11.73 mmol) in MeOH (30mL) at 0 °C was added portion wise NaBH4 (0.887 g, 23.45 mmol). Cold bath was removed and the reaction was stirred for 1 hour. HCI on (1 M, 0.2mL) was then added cautiously to quench the reaction. The reaction mixture was then concentrated and diluted with EtOAc (50mL) and water (10mL). The phases were separated and the aqueous layer was extracted with EtOAc (2x20mL). The combined organics were then dried (Na2804) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired t as a white solid (2.12 g). LCMS m/z 204.1 (M + H)+, Rt 0.69 min.
Intermediate 173: tert-butyl ((3S)hydroxymethylpentanyl)carbamate Step 1: Preparation of tert-butyl 1-(methoxy(methyl)amino)methyloxopropan- rbamate To a solution of (S)(tert-butoxycarbonylamino)methylbutanoic acid (5.86 g, 27.0 mmol) in DCM (100mL) at 0 °C was added portion wise di(1H-imidazolyl)methanone (4.81 g, 29.7 mmol). Cold bath was removed and the reaction was stirred at 20 °C for s. O,N-dimethylhydroxylamine hydrochloride (3.16 g, 32.4 mmol) was then added and followed by slow addition of triethylamine (3.28 g, 32.4 mmol). The reaction mixture was stirred at 20 °C for overnight (18 hr), and diluted with DCM (200mL) and washed with HCI (1 M, 2x50mL) and saturated NaHCO3 solution (2x50mL), H2O (50mL) and brine (50mL). The organic was then dried (Na2804) and concentrated under reduced pressure to give crude t (6.61 g). LCMS m/z 261.2 (M + H)+, Rt 0.77 min.
Step 2: Preparation of (S)-tert-butyl 2-methyloxopentanylcarbamate To a solution of (S)—tert-butyl 1-(methoxy(methyl)amino)—3-methyloxobutan ylcarbamate (4.23 g, 16.25 mmol) in THF (100 mL) at -70 0C was added drop wise methyl m (1.071 g, 48.7 mmol). Cold bath was replaced with -40 °C bath (MeCN in dry ice) removed and the reaction was stirred for 4 hours. Saturated NH4C| solution (10mL) was then added cautiously to quench the reaction. The on mixture was then allowed to warm to room temperature, and diluted with EtOAc (100mL) and water (50mL). The phases were separated and the aqueous layer was extracted with EtOAc (2x100mL). The combined organics were then dried 4) and concentrated under reduced pressure. The residue was ed via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (3.01 g). LCMS m/z 238.2 (M + Na)+, Rt 0.78 min.
Step 3: Preparation of tert-butyl 3-hydroxymethylbutanylcarbamate To a solution of (S)-tert-butyl 2-methyloxopentanylcarbamate (2.65 g, 12.31 mmol) in MeOH (30mL) at 0 °C was added portion wise NaBH4 (0.931 g, 24.62 mmol). Cold bath was removed and the reaction was stirred for 1 hour. HCI solution (1 M, 0.3 mL) was then added cautiously to quench the reaction. The reaction mixture was then concentrated and d with EtOAc (50mL) and water (10mL). The phases were separated and the aqueous layer was extracted with EtOAc L). The combined organics were then dried (Na2804) and concentrated. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.05 g). LCMS m/z 240.2 (M + Na)+, Rt 0.69 min.
Intermediate 174: (S)-tert-butyl (1-cyc|opropylhydroxyethyl)carbamate [Boo HN OH Step 1: Preparation of utyl 1-(methoxy(methyl)amino)methyloxopropan- 2-ylcarbamate To (S)(tert-butoxycarbonylamino)cyc|opropylacetic acid (5.01 g, 23.28 mmol) in MeOH (50mL) was added drop wise trimethylsilyldiazomethane (18.62 mi, 37.2 mmol) until no bubbles. The reaction was stirred for 30 minutes and quenched with drops of HOAc (0.1 mL). The reaction e was then concentrated under reduced pressure to give crude product as a light tan oil (5.35 g). LCMS m/z 252.1 (M + Na)+, Rt 0.77 min.
Step 2: ation of (S)-tert-butyl (1-cyc|opropylhydroxyethyl)carbamate To a solution of thyl 2-(tert-butoxycarbonylamino)cyclopropylacetate (5.35 g, 23.33 mmol) in EtZO (100 ml) was added LiBH4 (0.762 g, 35.0 mmol), followed by drop wise addition of methanol (1.420 mi, 35.0 mmol). The reaction was refluxed at 40 °C for one hour. The reaction mixture was then cooled to 0 °C, and ed with HCI (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3x100mL). The organic was then dried (Na2804) and concentrated under reduced pressure to give final crude product (4.16 g). LCMS m/z 224.1 (M + Na)+, Rt 0.62 min.
Intermediate 175: (R)-N-((S)(2-fluoro(1-methylcyclopropyl)phenyl)ethyl)—2- methylpropanesulfinamide X wH Step 1 To an oven dried round bottom flask with stir bar was added 4-bromo—2- fluorobenzaldehyde (5 g, 24.6 mmol), (R)methylpropanesulfinamide (3.28 g, 27.1 mmol) and DOE (49 mL). To this mixture was then added copper (ll) sulfate (5.90 g, 36.9 mmol). Reaction mixture was heated in a preheated oil bath to 55 °C for 18 hours.
Reaction mixture was filtered through a pad celite, washing the solids with CH2C|2. The filtrate was concentrated to afford a viscous yellow oil of N-(4-bromo—2- fluorobenzylidene)—2-methylpropanesulfinamide (7.73 g, 25.2 mmol, 103 % yield). 1H NMR (400 MHz, CDCL3) 8 1.27 (s, 9 H) 7.31 - 7.42 (m, 2 H) 7.87 (t, J=7.87 Hz, 1 H) 8.83 (s, 1 H). LCMS m/z 307.9 (M + H)+, Rt 1.01 min.
Step 2 To a solution of (R,E)—N-(4-bromofluorobenzylidene)—2-methylpropanesulfinamide (7.73 g, 25.2 mmol) in CH2C|2 (252 mL), cooled to 0°C (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33.7 mL, 101 mmol) in EtZO. Reaction mixture allowed to stir for 30 min at 0°C, then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0°C then ed with the slow addition of a saturated on of NH4CI. Aqueous e extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column tography (EtOAc/Heptane 40 to 100%) provided (R)-N-((S)(4-bromo fluorophenyl)ethyl)methylpropanesulfinamide (4.93 g, 15.3 mmol, 60% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCL3) 8 1.20 (s, 9 H) 1.56 (d, J=6.70 Hz, 3 H) 3.34 (br. s., 1 H) 4.77 - 4.87 (m, 1 H) 7.19 - 7.31 (m, 3 H). LCMS m/z 324.0 (M + H)+, Rt 0.90 min.
Step 3 To a microwave vial with stir bar was added ((S)(4-bromofluorophenyl)ethyl)— 2-methylpropane—2- (1 g, 3.10 mmol), isopropenyl boronic acid pinacol ester (1.51 ml, 8.07 mmol), DME (8 ml), sodium carbonate (7.76 mi, 15.5 mmol) (2.0 M aq) and dppf). CH2C|2 adduct (0.127 g, 0.155 mmol). Vessel was capped and heated by microwave ation for 20 min at 100 °C. Reaction mixture was diluted with a saturated solution of NH4CI. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (NaZSO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 50 to 100%) provided (R)-N-((S)(2-fluoro(propeny|)phenyl)ethyl)methylpropanesulfinamide (830 mg, 2.93 mmol, 94 % yield) as a pale brown crystalline. 1H NMR (400 MHz, DMSO) 81.08 -1.11 (m, 9 H) 1.47 (d, J=6.80 Hz, 3 H) 2.09 (d, J=0.54 Hz, 3 H) 4.61 - 4.71 (m, 1 H) 5.14 (t, J=1.32 Hz, 1 H) 5.43 (d, J=5.58 Hz, 1 H) 5.49 (s, 1 H) 7.24 - 7.30 (m, 1 H) 7.31 - 7.36 (m, 1 H) 7.41 - 7.47 (m, 1 H). LCMS m/z 284.0 (M + H)+, Rt 0.93 min.
Step 4 To a round bottom flask containing (R)-N-((S)(2-fluoro(propenyl)phenyl)ethyl)- 2-methylpropane—2- (0.37 g, 1.31 mmol) in DOE (13 mL) at 0 °C was added under argon diethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) followed by the dropwise addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. on mixture was cooled to 0 °C whereupon a second addition of diethylzinc (1.0M in hexanes) (13.1 mL, 13.1 mmol) took place followed by the addition of chloroiodomethane (0.95 mL, 13.1 mmol). Reaction mixture allowed to warm to room temperature and stirred 18 hours under argon. Reaction mixture was cooled to 0 °C in a ice bath and to the cold reaction mixture was slowly added a saturated solution of NH4CI. The aqueous mixture was extracted with EtOAc.
Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and trated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 20 to 100%) provided a white crystalline of (R)-N-((S)(2-fluoro(1- methylcyclopropyl)phenyl)ethyl)methylpropanesulfinamide (89 mg, 0.299 mmol, 22.92 % yield). 1H NMR (400 MHz, CDCL3) 8 0.75 - 0.79 (m, 2 H) 0.85 - 0.90 (m, 2 H) 1.20 (s, 9 H) 1.55 (s, 3 H) 1.57 (d, J=6.80 Hz, 1 H) 3.34 (d, J=5.23 Hz, 1 H) 4.75 - 4.85 (m, 1 H) 6.90 (dd, J=12.30, 1.74 Hz, 1 H) 6.97 (dd, J=8.05, 1.78 Hz, 1 H) 7.22 (t, J=7.97 Hz, 1 H). LCMS m/z 298.1 (M + H)+, Rt 1.01 min.
The Intermediates in Table 4k were prepared by a method similar to the one described for the ation of Intermediate 175.
Table 4k Intermediate 176 Intermediate 177 Table 4m. Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed in Table 4k. 176: (R)—2-methyl-N-((S)—1-(6- MS m/z (1-methylcyclopropyl)pyridin 282.1 (M + yl)ethyl) propanesulfinamide H)+, Rt 0.48 min. 177: (R)—2-methyl-N-((S)—1-(4- ) 0.71 - 0.76 (m, 2 H) 0.85 - MS m/z (1-methylcyclopropyl) 0.89 (m, 2 H) 1.20 - 1.22 (m, 9 H) 1.41 280.1 (M + phenyl)ethyl) propane (s, 3 H) 1.53 (d, J=6.65 Hz, 3 H) 3.29 H)+, Rt 0.98 sulfinamide (d, J=3.57 Hz, 1 H) 4.50 - 4.57 (m, 1 min.
H) 7.21 (s, 2 H) 7.23 (s, 2 H) Intermediate 178: (R)—N-((S)—1-(4-(1-ethoxycyclopropyl)fluorophenyl)ethyl)—2- propanesulfinamide >(S'NH Step1 To a microwave vial with stir bar was added (R)—N-((S)—1-(4-bromofluorophenyl)ethyl)— 2-methylpropanesuIfinamide (500 mg, 1.55 mmol) followed by the on of tributyl(1-ethoxyvinyl)stannane (1.12 g, 3.10 mmol), triethylamine (0.65 ml, 4.65 mmol) and PdCl2(dppf). CH2C|2 adduct (63 mg, 0.078 mmol). To the solids was added toluene (10 ml). Vial capped and heated in a preheated sand bath at 100 °C for 1 hour.
Reaction mixture was loaded onto silica gel column. Silica gel column chromatography (MeOH/ CH2C|2 0 to 10% with 1% NH4OH buffer) provided (R)—N-((S)(4-(1- vinyl)fluorophenyl)ethyl)methylpropanesulfinamide (498 mg, 1.59 mmol, 102 % yield) as a brown viscous oil which crystallizes upon standing. 1H NMR (400 MHz, CDCL3) 8 1.20 (s, 9 H) 1.43 (t, J=6.97 Hz, 3 H) 1.58 (d, J=6.75 Hz, 3 H) 3.35 (d, J=4.74 Hz, 1 H) 3.92 (q, J=6.96 Hz, 2H) 4.23 (d, J=2.79 Hz, 1 H) 4.65 (d, J=2.79 Hz, 1 H) 4.79 - 4.89 (m, 1 H) 7.16 - 7.20 (m, 1 H) 7.29 - 7.34 (m, 1 H) 7.39 (dd, J=8.07, 1.66 Hz, 1 H).
Step 2 To a round bottom flask containing (R)—N-((S)—1-(4-(1-ethoxyvinyl)fluorophenyl)ethyl)- 2-methylpropane—2-sulfinamide (0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, .6 mmol) in toluene (15 mL) at 0 °C under argon was added diethylzinc (1.0M in hexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to room ature and stirred for 1 hour. Reaction mixture was cooled to 0 °C in an ice bath and to the cold reaction mixture was slowly added a saturated solution of NH4CI. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2804), filtered and concentrated onto silica gel. Silica gel column chromatography CH2C|2 0 to 10%) provided (R)—N-((S)—1-(4-(1-ethoxycyclopropyl) fluorophenyl)ethyl)methy|propanesulfinamide (145 mg, 0.44 mmol, 28 % yield) as a viscous brown oil. 1H NMR (300 MHz, CDCL3) 8 0.93 - 0.99 (m, 2 H) 1.14 - 1.20 (m, 3 H) 1.21 (s, 9 H) 1.22 - 1.27 (m, 2 H) 1.57 - 1.61 (m, 4 H) 3.35 (d, J=4.98 Hz, 1 H) 3.45 (q, J=7.07 Hz, 2 H) 4.77 - 4.87 (m, 1 H) 6.98 (dd, J=7.58, 1.43 Hz, 3 H) 7.00 - 7.03 (m, 4 H) 7.28 - 7.32 (m, 1 H). LCMS m/z 328.1 (M + H)+, Rt 0.95 min.
The Intermediate in Table 4n were prepared by a method r to the one described for the preparation of Intermediate 178.
Table 4n.
Intermediate 179 ediate 180 Intermediate 181 2012/055133 Table 4p. Chemical name, NMR chemical shifts and LCMS signal for each intermediate listed in Table 4n. 179: (R)—N-((S)(2,5-dif|uoro MS m/z 304.2 isopropylphenyl)ethyl)—2- (M + H)+, Rt methylpropanesulfinamid 1.04 min. 180: (R)—N-((S)(4-bromo-2,5- MS m/z 340.1, difluorophenyl)ethyl)—2- 342.1 (M + propanesulfinamide H)+, Rt 0.96 min. 181: (R)—N-((S)(6-(1- MS m/z ethoxycyclopropyl)pyridin 311.1 (M + yl)ethyl)methy|propane H)+, Rt 0.52 sulfinamide min.
Intermediate 182: (R)—N-((S)—1-(4-(1-cyanocyclopropyl)fluorophenyl)ethyl) methylpropanesulfinamide Step1 To a microwave vial with a stir bar was added (R)—N-((S)—1-(4-bromo fluorophenyl)ethyl)methy|propanesulfinamide (300 mg, 0.93 mmol), 4- isoxazoleboronic acid pinacol ester (218 mg, 1.12 mmol), PdC|2(dppf).CH2C|2 adduct (76 mg, 0.09 mmol), potassium fluoride (2.7 mL, 1.0 M in water, 2.79 mmol) and finally DMSO (9 mL). The reaction mixture was degassed with bubbling nitrogen (3 min) and the vial capped and heated in a ted oil bath at 130 °C for 18 hours. The reaction mixture was diluted with a saturated solution of NH4C| and extracted with EtOAc.
Organic phases combined, washed with water, brine, dried (Na2804), filtered and concentrated onto silica gel. Silica gel column tography (EtOAc/Heptanes 40 to 100%) provided (R)—N-((S)—1-(4-(cyanomethy|)f|uorophenyl)ethyl)methy|propane sulfinamide (136 mg, 0.48 mmol, 52 % yield) as a viscous brown oil. 1H NMR (400 MHz, CDCL3) 8 1.19 (s, 9 H) 1.57 (d, J=6.80 Hz, 3 H) 3.39 (d, J=4.35 Hz, 1 H) 3.74 (s, 2 H) 4.81 - 4.88 (m, 1 H) 7.04 (d, J=10.66 Hz, 1 H) 7.11 (d, J=7.97 Hz, 1 H) 7.38 (t, J=7.73 Hz, 1 H). LCMS m/z 283.0 (M + H)+, Rt 0.72 min.
Step 2 To a scintillation vial containing (R)—N-((S)—1-(4-(cyanomethyl)f|uorophenyl)ethyl) methylpropane (86 mg, 0.31 mmol) and a stir bar was added toluene (2 mL). To this mixture was then added tetrabutylammonium e (19 mg, 0.06 mmol) followed by the addition of NaOH (1.52 ml, 1.0 M (aq), 1.52 mmol) and bromoethane (0.11 ml, 1.22 mmol). Vial capped and reaction mixture was stirred vigorously at room temperature for 18 hours. Whereupon, 1,2-dibromoethane (0.11 ml, 1.22 mmol) and tetrabutylammonium bromide (19 mg, 0.06 mmol) were added and reaction mixture allowed to stir an onal 18 hours. A third addition of 1,2-dibromoethane (0.11 ml, 1.22 mmol) was added and the reaction mixture heated to 50 °C for an additional 18 hours in a preheated aluminum tray. The reaction mixture was quenched with a ted solution of NH4C| and the aqueous mixture extracted with EtOAc. cs combined and washed twice with water, brine, dried (Na2804), filtered and trated. Crude material was passed h a small plug of silica gel using %MeOH:90%DCM to elute product. The solution was concentrated to afford a viscous orange oil of (R)—N-((S)—1-(4-(1-cyanocyclopropyl)f|uorophenyl)ethyl) methylpropanesulfinamide (23 mg, 0.08 mmol, 24 % yield). 1H NMR (400 MHz, CDCL3) 8 1.20 (s, 9 H) 1.38 - 1.44 (m, 2 H) 1.56 (d, J=6.75 Hz, 3 H) 1.73 - 1.79 (m, 2 H) 3.37 (d, J=4.45 Hz, 1 H) 4.78 - 4.88 (m, 1 H) 6.94 (dd, J=11.35, 1.91 Hz, 1 H) 7.09 (dd, J=8.07, 1.91 Hz, 1 H) 7.34 (t, J=7.90 Hz, 1 H). LCMS m/z 309.2 (M + H)+, Rt 0.83 min.
Intermediate 183: (R)—N-((S)—1-(2-fluoroisopropylphenyl)ethyl)methy|propane sulfinamide >( wH To a round bottom flask containing (R)—N-((S)—1-(2-fluoro(propenyl)phenyl)ethyl)- 2-methylpropanesu|finamide (204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To this solution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH (1 mL). A hydrogen atmosphere was inserted and the resulting reaction mixture d at room temperature for 18 hours, at which time more palladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogen atmosphere was inserted again and the reaction mixture allowed to stir an additional 18 hours at room temperature. The reaction mixture was filtered through a syringe filter and concentrated to afford a light brown viscous oil of (R)—N-((S)—1-(2-fluoroisopropylphenyl)ethyl)methylpropane sulfinamide (149 mg, 0.52 mmol, 73 % yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCI3) 8 1.20 (s, 9 H) 1.24 (d, J=5.87 Hz, 6 H) 1.58 (d, J=6.70 Hz, 3 H) 2.89 (dt, J=13.79, 6.90 Hz, 1 H) 3.35 (d, J=5.04 Hz, 1 H) 4.76 - 4.85 (m, 1 H) 6.90 (dd, J=12.03, 1.52 Hz, 1 H) 6.98 (dd, J=7.90, 1.54 Hz, 1 H) 7.24 (t, J=7.97 Hz, 1 H). LCMS m/z 286.3 (M + H)+, Rt 1.01 min.
Intermediate 184: (R)—N-((S)—1-(4-cyclopropy|—2-fluorophenyl)ethyl)methylpropane sulfinamide >(S'NH To a microwave vial containing a stir bar was added (R)—N-((S)—1-(4-bromo fluorophenyl) ethyl)methylpropanesulfinamide (100 mg, 0.31 mmol) followed by the addition of ium cyc|opropyltrifluoroborate (459 mg, 3.10 mmol), cesium carbonate (506 mg, 1.55 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) and di(1-adamanty|)-n- butylphosphine (22 mg, 0.06 mmol), toluene (2.6 mL) and finally water (0.5 mL). The vial capped and heated by microwave irraditation for 20 min at 100 °C, ed by thermal heating at 100°C in a preheated aluminum tray for 18 hours. The reaction mixture was diluted with a saturated solution of NH4CI. The aqueous mixture extracted with EtOAc.
Organic phases combined, washed with water, brine, dried (Na2804), filtered and concentrated to afford a yellow crystalline of (R)—N-((S)(4-cyc|opropy| fluorophenyl)ethyl)methylpropanesulfinamide (116 mg, 0.33 mmol, 106 % yield).
LCMS m/z 284.0 (M + H)+, Rt 0.90 min.
Intermediate 185: ((S)—1-(6-cyclopropy|pyridinyl)ethyl)methylpropane sulfinamide 'N(8) \ H | ((S)—1-(6-cyclopropylpyridinyl)ethyl)methylpropanesulfinamide is ed with a method similar to that used to access Intermediate 184. MS m/z 267.1 (M + H)+, Rt 0.44 min.
Intermediate 186: (R)—N-((S)—1-(2-fluoro(1-methyl-1H-pyrazolyl)phenyl)ethyl)—2- methylpropanesulfinamide X wH To a two microwave vials with stir bars were added (R)—N-((S)—1-(4-bromo fluorophenyl)ethyl)methylpropanesulfinamide (1.5 g, 4.65 mmol), 1-methyl1H- pyrazoleboronic acid pinacol ester (2.91 g, 13.9 mmol), DME (20 mL), sodium carbonate (11.6 mL, 23.3 mmol, 2.0 M aq) and PdCl2(dppf).CH2C|2 adduct (190 mg, 0.23 mmol) divided between the two vials. The vials were capped and heated by microwave irradiation for 20 min at 100 °C respectively. The reaction mixtures combined, diluted with a saturated solution of NH4C| and EtOAc. The phases were partitioned and the aqueous phase extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2804), filtered and trated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided a orange crystalline of (R)—N- ((S)(2-fluoro(1-methyl-1H-pyrazolyl)phenyl)ethyl)methylpropanesulfinamide (1.07 g, 3.31 mmol, 71 % yield. 1H NMR (400 MHz, CDCL3) 8 ppm 1.21 (s, 9 H) 1.60 (d, J=6.80 Hz, 3 H) 3.36 (d, J=4.25 Hz, 1 H) 3.96 (s, 3 H) 4.79 - 4.91 (m, 1 H) 7.13 (dd, 9, 1.61 Hz, 1 H) 7.23 (dd, J=8.00, 1.64 Hz, 1 H) 7.30 - 7.37 (m, 1 H) 7.60 (s, 1 H) 7.74 (s, 1 H). LCMS m/z 324.0 (M + H)+, Rt 0.74 min.
The Intermediates in Table 4q were prepared by a method similar to the one described for the preparation of ediate 186.
Table 4q. _ntermediate187 ediate188 _ntermediate189 Table 4r. Chemical name, NMR al shifts and LCMS signal for each intermediate listed in Table 4q. 187: (R)—2-methy|-N-((S)—1-(4- MS m/z (1-methyl-1H-pyrazol 306.0 (M + yl)phenyl)ethyl)propane H)+, Rt 0.71 sulfinamide min. 188: ((S)—1-(4-(1,5- MS m/z dimethyl-1H-pyrazol 320.0 (M + yl)phenyl)ethyl)—2- H)+, Rt 0.72 methylpropanesulfinamide min. 189: ((S)(2-f|uoro (DMSO) 1.10 (s, 9 H) 1.47 (d, J=6.75 MS m/z (1H-pyrazolyl)phenyl)ethyl)— Hz, 3 H) 4.60 - 4.70 (m, 1 H) 5.41 (d, 310.0 (M + 2-methylpropanesulfinamide J=5.48 Hz, 1 H) 7.38 - 7.44 (m, 3 H) H)+, Rt 0.67 7.96 (br. s., 1 H) 8.23 (br. s., 1 H) min. 12.97 (br. s., 1 H) Intermediate 190: (R)—N-((S)—1-(2-f|uoro(trifluoromethyl)phenyl)ethyl)—2- methylpropanesulfinamide >( 'N H F Step 1 To a oven dried round bottom flask with stir bar was added 2-f|uoro(trifluoromethyl) benzaldehyde (5 g, 26.0 mmol), (R)—2-methylpropanesulfinamide (3.47 g, 28.6 mmol) and DOE (52 mL). To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol). The reaction mixture was heated in a preheated oil bath at 55 °C for 18 hours.
The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green 0” of (R,E)—N-(2-f|uoro (trifluoromethyl)benzylidene)—2-methyl propanesulfinamide (7.3 g, 24.7 mmol, 95 % yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCI3) 8 ppm 1.29 (s, 9 H) 7.44 (d, J=10.08 Hz, 1 H) 7.51 (d, J=8.27 Hz, 1 H) 8.13 (t, J=7.46 Hz, 1 H) 8.92 (s, 1 H). LCMS m/z 296.0 (M + H)+, Rt 1.02 min.
Step 2 2012/055133 To a solution of N-(2-fluoro(trifluoromethyl)benzylidene)methylpropane amide (7.3 g, 24.7 mmol) in CH2C|2 (247 mL) cooled to 0°C (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33 mL, 99 mmol) in EtZO.
Reaction mixture allowed to stir for 30 min at 0°C, then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0°C then quenched with the slow addition of a saturated solution of NH4CI.
Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2804), filtered and trated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)—N-((S)—1-(2-fluoro (trifluoromethyl)phenyl)ethyl)methy|propanesulfinamide (4.68 g, 15.0 mmol, 61% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCL3) 8 1.22 (s, 9 H) 1.60 (d, J=6.80 Hz, 3 H) 3.38 (d, J=4.01 Hz, 1 H) 4.87 - 4.97 (m, 1 H) 7.33 (d, J=10.32 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.49 - 7.55 (m, 1 H). LCMS m/z 312.0 (M + H)+, Rt 0.92 min.
Intermediate 191: (R)—N-((S)—1-(6-tert-buty|pyridinyl)ethyl)methylpropane sulfinamide 8'N (S) \ H | ((S)—1-(6-tert-butylpyridinyl)ethyl)methylpropanesulfinamide is prepared with methods similar to those used to prepare Intermediate 190. 1H NMR (400 MHz, CDCI3) 5 1.22 (s, 9 H) 1.37 (s, 9 H) 1.57 (d, J=6.75 Hz, 3 H) 3.31 (d, J=3.37 Hz, 1 H) 4.56 - 4.65 (m, 1 H) 7.32 (d, J=8.22 Hz, 1 H) 7.57 (dd, J=8.24, 2.23 Hz, 1 H) 8.54 (d, J=2.05 Hz, 1 H). MS m/z 283.1 (M + H)+, Rt 0.51 min.
Intermediate 192: (S)-tert-butyl 1-(3-chloro(cyclopentylcarbamoyl)phenyl)ethy| carbamate w.0 a H o Step 1 To a round bottom flask with stir bar was added 4-((S)-1aminoethylchlorobenzoic acid HCI salt (1.05 g, 4.45 mmol) followed by the addition of THF (40 mL). To this solution was added DIEA (1.86 ml, 10.7 mmol). The reaction mixture becomes cloudy white followed by the addition of t-butyl dicarbonate (1.07 g, 4.89 mmol). Resulting reaction mixture allowed to stir for 18 hours at room ature. At which time the reaction mixture was then heated to 60 °C for 2 hours in a oil bath. t-butyl dicarbonate (1.07 g, 4.89 mmol) and NMP (20 ml) were then added and the resulting reaction mixture allowed to stir for 2 hours at 60 °C. Volatiles were removed. The ing oil was diluted with a saturated solution of NH4C| and the aqueous mixture extracted with EtOAc.
The organic phases combined, washed twice with water, brine, dried (Na2804), filtered and concentrated to a viscous yellow oil of (S)(1-(tert-butoxycarbonylamino)ethyl)—2- chlorobenzoic acid (2.32 g, 6.19 mmol, 139 % yield) which contains some excess di-tert- butyl onate and NMP. LCMS m/z 284.9 (M + H)+(carboxylic acid fragment + CH3CN adduct), Rt 0.75 min.
Step2 To a round bottom flask with stir bar was added (S)(1-(tert- butoxycarbonylamino)ethyl)chlorobenzoic acid (450 mg, 1.20 mmol), cyclopentylamine (355 uL, 3.60 mmol), EDC HCI (460 mg, 2.40 mmol), 1-hydroxyaza- benzotriazole (229 mg, 1.68 mmol) and DMF (6 mL). To this mixture was then added DIEA (629 uL, 3.60 mmol). on mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with twice with water, brine, dried (Na2804), filtered and concentrated to a brown crystalline of (S)-tert-butyl 1-(3-chloro (cyclopentylcarbamoyl) phenyl)ethylcarbamate (476 mg, 1.17 mmol, 97 % . LCMS m/z 367.0 (M + H)+, Rt 0.90 min.
The Intermediates in Table 4s were prepared by a method similar to the one described for the ation of Intermediate 192. 1 16 Table 4s.
Intermediate 193 Intermediate 194 Table 4t. Chemical name and LCMS signal for each intermediate listed in Table 4s.
Intermediate: Name 193: (S)-tert-butyl 1-(3-chloro MS m/z (cyclohexyl carbamoyl) phenyl) 381.1 (M + ethylcarbamate H)+, Rt 0.96 min. 194: tert-butyl (S)—1-(3-chloro MS m/Z S)—4-hydroxycyclohexyl 391_1 (M + carbamoyl)phenyl)ethylcarbamate H)+, Rt 0_71 min.
Intermediate 195: (S)-tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate ADA”O A slurry of (1-aminoethyl)phenol (1.188 g, 6.84 mmol) and Boc20 (1.747 mL, 7.53 mmol) in DCM (17.10 mL) was stirred at room temperature under N2 while slowly adding DIEA (1.434 mL, 8.21 mmol). The initially insoluble starting materials slowly dissolve.
The solution was stirred at room temperature for 16 hours and then concentrated. The oily residue was solved in EtOAc and washed with Na2CO3 saturated, followed by brine. The original aqueous layer was re-extracted with EtOAc, which was then washed with brine and combined with the previous EtOAc batch. The combined organics were dried over Na2804, filtered and concentrated to 2.4g crude clear yellowish oil which was purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%), ng (S)- utyl 1-(3-hydroxypheny|)ethy|carbamate as a clear colourless oil, which solidifies upon sitting (1.79 g, 7.55 mmol, 110 % yield). 1H NMR (400 MHz, CDCL3) 8 1.44 (br. s., 12 H) 4.08 - 4.18 (m, 1 H) 4.76 (br. s., 1 H) 6.72 (dd, J=7.46, 1.83 HZ, 1 H) 6.78 (br. s., 1 H) 6.88 (br. s., 1 H) 7.16 - 7.24 (m, 1 H). LCMS m/Z 182.0 (the parent not observed, just the Boc fragments) (M + H)+, Rt 0.71 min.
Intermediate 196: (S)(3-(cyclopentyloxy)phenyl)ethanamine hydrochloride Step 1: Mitsunobu A To a solution of (S)-tert—butyl 1-(3-hydroxyphenyl)ethylcarbamate (107.5 mg, 0.453 mmol), PPh3 (238 mg, 0.906 mmol) and cyclopentanol (0.164 ml, 1.812 mmol) in THF (2 ml) at room ature was added DEAD (0.143 ml, 0.906 mmol) dropwise under N2.
The resulting yellow solution was stirred for 4 hours and then concentrated. The viscous yellow oil was re-dissolved in DMSO and purified by reverse phase HPLC. The combined t fractions were desalted by addition of equal amount of EtOAc and about 250mg Na2C03 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)—tert-butyl cyclopentyloxy)phenyl)ethylcarbamate (75.1 mg, 0.246 mmol, 54.3 % yield) as a white solid film. LCMS m/z 291 .1/250.0 (the parent not observed, just the Boc fragments) (M + H)+, Rt 1.07 min.
Step 2 rt-butyl 1-(3-(cyclopenty|oxy)phenyl)ethylcarbamate (75.1 mg, 0.246 mmol) was dissolved in 4M HCI in dioxane (1 ml, 4.00 mmol) and the resulting mixture was allowed to sit for 1hour, then concentrated to yield (S)—1-(3-(cyclopentyloxy)phenyl)ethanamine as an HCI salt (yield assumed quantitative). LCMS m/z 206.1 (M + H)+, Rt 0.61 min.
Intermediate 197: (S)(3-(cyclohexyloxy)phenyl)ethanamine hydrochloride Step 1: Mitsunobu B To a solution of (S)—tert-butyl 1-(3-hydroxyphenyl)ethylcarbamate (100 mg, 0.421 mmol), cyclohexanol (0.180 ml, 1.686 mmol) and PPh3 (221 mg, 0.843 mmol) in THF (2 ml), was added DEAD (0.133 ml, 0.843 mmol) dropwise, under N2, at room temperature. The resulting yellow solution was stirred for 3 hours, at which point r batch of cyclohexanol (0.180 ml, 1.686 mmol), PPh3 (221 mg, 0.843 mmol), and 10min later DEAD (0.133 ml, 0.843 mmol), was added at room temperature. The on e was stirred for 16 hours and then concentrated. The crude clear 0” was re—dissolved in DMSO and purified by reverse phase HPLC. The combined product fractions were desalted by on of equal amount of EtOAc and about 250mg Na2C03 in a separatory funnel. The phases were separated and the c washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-tert-buty| 1-(3- (cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol, 55.0 % yield) as a clear colourless film. LCMS m/z 3050/2640 (the parent not observed, just the Boc fragments) (M + H)+, Rt 1.12 min.
Step 2 (S)—tert-butyl 1-(3-(cyclohexyloxy)phenyl)ethylcarbamate (74.1 mg, 0.232 mmol) was dissolved in 4M HCI in dioxane (1 ml, 4.00 mmol) and the resulting mixture was allowed to sit for 1 hour, then concentrated to yield (S)(3-(cyclohexyloxy)phenyl)ethanamine as an HCI salt (yield assumed quantitative). LCMS m/z 220.1 (M + H)+, Rt 0.66 min.
The Intermediates in Table 4v were prepared using either the method described for the preparation of Intermediate 196 or Intermediate 197.
Table 4v.
Intermediate: Name LCMS 198: (3- MS m/z 206.1 (M + (cyclopentyloxy)pheny|)ethanamine H)+, Rt 0.61 min. 199: (S)(3- MS m/z 220.1 (M + (cyclohexyloxy)phenyl)ethanamine H)+, Rt 0.66 min. 200: (S)(3- MS m/z 234.1 (M + (cycloheptyloxy)phenyl)ethanamine H)+, Rt 0.73 min. 201: (S)(3- MS m/z 180.1 (M + isopropoxyphenyl)ethanamine H)+, Rt 0.50 min. 202: (S)(3- MS m/z 194.1 (M + isobutoxyphenyl)ethanamine H)+, Rt 0.61 min. 203: (S)(3-((S)—tetrahydrofuran- MS m/z 208.1 (M + 3-yloxy)phenyl)ethanamine H)+, Rt 0.41 min. 204: -(3-(tetrahydro—2H- MS m/z 222.1 (M + pyranyloxy)phenyl)ethanamine H)+, Rt 0.46 min.
Intermediate 205: (S)(3-phenoxyphenyl)ethanamine AGE) Into a 20ml microwave vial was weighted 1-(pyridinyl)propanone ligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg, 0.332 mmol) and Cs2003 (2166 mg, 6.65 mmol). To the mixture was added DMSO (5 ml) and (S)—1-(3- bromophenyl)ethanamine (0.5 ml, 3.32 mmol). The tube was flushed with N2, capped, and the black mixture heated in the oil bath at 90°C for 18 hours. The heterogenous e was diluted with EtOAc and filtered through a glass-fritted funnel, eluting with EtOAc and another 5mls of DMSO. The volatiles were then removed in vacuo and the crude brown liquid was ed through 1pm PTFE filter and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250mg Na2003 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, ed and concentrated in vacuo to yield (S)(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5 % yield) as an amber oil. LCMS m/z 214.1 (M + H)+, Rt 0.61 min.
Intermediate 206: (S)(2,3-dif|uoropheny|)ethanamine Step 1 To a oven dried round bottom flask with stir bar was added 2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol), (R)—2-methylpropanesulfinamide (0.469 g, 3.87 mmol) and DOE (7.04 mL). To this mixture was then added Copper (ll) Sulfate (0.842 g, 5.28 mmol).
Reaction mixture heated in a preheated oil bath to 55 °C for 24 hours. The on mixture was filtered through a celite pad washing solids with DCE. Combined filtrate was concentrated to afford a viscous yellow oil of (R,E)—N-(2,3-difluorobenzylidene)—2- methylpropanesulfinamide 7 g, 3.26 mmol, 93 % yield). LCMS m/z 246.1 (M + H)+, Rt0.91 min.
Step 2 To a solution of (R,E)—N-(2,3-difluorobenzylidene)methylpropanesulfinamide (0.800 g, 3.26 mmol) in DCM (32.6 mL), cooled to 0°C (water/icebath) under N2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in l ether. Reaction mixture allowed to stir for 30 min at 0 °C. Then gradually allowed to warm to room temperature and d for 30min at room temperature. Reaction mixture was cooled to 0 °C then ed with the slow addition of a saturated solution of NH4C| and diluted with EtOAc. Phases partitioned aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried with MgSO4, ed and concentrated to afford (R)-N-((S)(2,3- difluorophenyl)ethyl)methylpropanesulfinamide (0.7868 g, 3.01 mmol, 92 % yield) as yellow solid. LCMS m/z 262.0 (M + H)+, Rt 0.70 min.
Step 3 To a round bottom flask containing (R)-N-((S)(2,3-difluorophenyl)ethyl)—2- methylpropanesulfinamide (786.8 mg, 3.01 mmol) was added Dioxane (10.000 mL).
To this solution was added HCl in dioxane 4.0M (1.505 mL, 6.02 mmol) and the solution was allowed to stir 15 min at room temperature. The reaction mixture was concentrated, dissolved in Et20 10 ml, and concentrated again. Et20 was again added and resulting mixture sonnicated and a solid al was filtered and dried to afford (S)—1-(2,3- difluorophenyl)ethanamine (0.4213 g, 2.176 mmol, 72.3 % yield) as a white crystalline HCl salt. 1H NMR (400 MHz, D20) d ppm 1.55 (d, J=6.99 Hz, 3 H) 4.71 (q, J=6.96 Hz, 1 H) 7.10 - 7.26 (m, 3 H); LCMS m/z 158.0 (M + H)+, Rt 0.37 min.
Intermediate 207: (S)(4-(difluoromethyl)f|uorophenyl)ethanamine WO 46136 Step 1: Preparation of 1-bromo(difluoromethyl)fluorobenzene A mixture of 4-bromofluorobenzaldehyde (2.03 g, 10 mmol) and (diethylamino)su|fur trifluoride (DAST; 1.32 mL, 10 mmol) is heated carefully until exothermic on occurs, then heated at 60 °C for 15 min, and allowed to cool to room temperature. The e was diluted with DCM (20 mL) and poured into ice/water (30 mL). The mixture was neutralized with NaHCO3 to ~pH 8. The separated aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over Na2804, filtered off, and concentrated under reduced pressure. The residue was purified by column tography [Si02, 40 g, heptane/ethyl acetate], providing 1-bromo (difluoromethyl)fluorobenzene (0.845 g) as a clear colorless oil.
Step 2: Preparation of luoromethyl)fluorobenzaldehyde To a solution of 1-bromo(difluoromethyl)—2-fluorobenzene (311 mg, 1.382 mmol) in THF (2.99 mL) was added ithium ( 1.6M solution in hexanes; 0.881 mL, 1.410 mmol) over ~5 min at -78 °C. The reaction mixture was stirred for 30 min at -78 °C then DMF (0.161 mL, 2.073 mmol) was added dropwise over ~1 min. Stirring was continued for 20 min. The reaction mixture was quenched with aqueous 1M HCI on/MeOH (2:1, 3 mL) and allowed to warm to room temperature. The e was diluted with 5 mL of water. The separated aqueous layer was with ether (5 mL). The combined organic layers were washed with 1M aqueous NaOH solution (10 mL) and saturated brine (10 mL), dried over MgSO4, filtered off and concentrated under reduced pressure. ed reaction with 420 mg of 1-bromo(difluoromethyl)fluorobenzene and combined crude materials for purification. The crude material was purified by column chromatography [Si02, 24 g, heptane/ethyl acetate], providing 4-(difluoromethyl)—2- fluorobenzaldehyde (162.8 mg) as a yellow oil.
Step 3: Preparation of (R,E)-N-(4-(difluoromethyl)f|uorobenzylidene) methylpropanesulfinamide To a mixture of 4-(difluoromethyl)—2-fluorobenzaldehyde (162 mg, 0.930 mmol) and (R)- 2-methylpropane—2-sulfinamide (124 mg, 1.023 mmol) in DOE (3 mL) was added copper sulfate (223 mg, 1.396 mmol). on mixture was heated in a preheated oil bath to 55 °C for 38 hours. The mixture was allowed to cool to room temperature, filtered through a pad of celites and washed with DCE. Combined filtrates were concentrated under reduced pressure to afford (R,E)—N-(4-(difluoromethyl)f|uorobenzylidene)—2- methylpropanesulfinamide (266 mg) as a yellow oil, which was used t further purification. LCMS m/z 278.1 (M + H)+, Rt 0.98 min.
Step 4: Preparation of (R)-N-((S)(4-(dif|uoromethyl)—2-fluorophenyl)ethyl) methylpropanesulfinamide To a solution of (R,E)-N-(4-(difluoromethyl)fluorobenzylidene)—2-methylpropane sulfinamide (266 mg, 0.959 mmol) in DCM (9.6 mL) was added magnesium bromide (3M in diethylether; 1.20 mL) at 0 °C. The reaction mixture was d to stir for 30 min at 0 oC, gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. The mixture was cooled to 0 °C, and carefully ed with saturated aqueous NH4C| solution (3 mL). The separated aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [Si02, 40 g, heptane/ethyl e], ing (R)—N- -(4-(difluoromethyl)fluorophenyl)ethyl)methylpropanesulfinamide (160.5 mg) as a white solid. LCMS m/z 294.5 (M + H)+, Rt 0.85 min.
Step 5: Preparation of (S)(4-(dif|uoromethyl)—2-fluorophenyl)ethanamine To (R)—N-((S)—1-(4-(difluoromethyl)fluorophenyl)ethyl)methylpropanesulfinamide (160 mg, 0.545 mmol) was added 4M HCI in dioxane (409 uL) to give a yellow solution.
The resulting mixture was stirred at room temperature for ~1hour. To the mixture was added slowly diethylether (~20 mL). The solids were filtered off, suspended in diethylether, filtered off and rinsed with diethylether, dried under reduced pressure providing (S)(4-(dif|uoromethyl)fluorophenyl)ethanamine (103 mg) as an off-white solid, which was used without r purification. LCMS m/z 190.1 (M + H)+, Rt 0.42 min.
Intermediate 208: (S)(4-(pyrimidinyloxy)phenyl)ethanamine Step 1: Preparation of imidinyloxy)benzaldehyde To a solution of pyrimidinol (500 mg, 5.20 mmol) in DMF (5.20 mL) under argon was added 4-fluorobenzaldehyde (0.558 mL, 5.20 mmol), sodium methanesulfinate (133 mg, 1.30 mmol), and potassium carbonate (1.079 g, 7.81 mmol). The reaction mixture was heated at 120 °C for 3 hour. The mixture was d to cool to room temperature and was diluted with water (25 mL). The mixture was extracted with EtOAc (2x 25 mL). The combined organic layers were washed with brine (2x 50 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [Si02, 24 g, e/ethyl acetate], providing 4-(pyrimidin y|oxy)benza|dehyde (666 mg) as a yellow solid. LCMS m/z 201.0 (M + H)+, Rt 0.52 min.
Step 2: Preparation of (R,E)methyl-N-(4-(pyrimidin y|oxy)benzylidene)propanesulfinamide A mixture of 4-(pyrimidinyloxy)benzaldehyde (666 mg, 3.33 mmol), (R)—(+)—tert- sulfinamide (450 mg, 3.71 mmol) and copper sulfate (796 mg, 4.99 mmol) in anhydrous in dichloroethane (7.648 mL) and under argon was heated at 55 °C for ~21 hours. The reaction mixture was allowed to cool to room ature. The slurry was filtered through a celite pad, eluted with DCM (5x 10 mL). The combined filtrates were concentrated under reduced pressure and the ing yellowish oil was purified by column chromatography [Si02, 24 g, heptane/ethyl acetate] providing (R,E)—2-methyl-N- (4-(pyrimidinyloxy)benzy|idene)propane—2-sulfinamide (836 mg) as a pale viscous oil.
LCMS m/z 304.0 (M + H)+, Rt 0.79 min.
Step 3: Preparation of 2-methyl-N-((S)(4-(pyrimidin y|oxy)phenyl)ethyl)propanesulfinamide A solution of (R,E)—2-methyl-N-(4-(pyrimidinyloxy)benzylidene)propanesulfinamide (830 mg, 2.74 mmol) in DCM (6.72 mL) was cooled to -40 °C. To the solution was added methylmagnesium bromide (3M in diethylether; 1.81 mL) dropwise over 10 min.
Additional DCM (5 mL) were added to retain stirring. The yellow sion was stirred at -40 °C for ~30 min while warming to -20 °C. The mixture was cooled to -40 °C and additional methylmagnesium bromide (3M in diethylether; 1.8 mL) was added. The suspension was stirred for ~3 hour while slowly warming to -20 °C. The mixture was cooled to ~-40 °C, and additional methylmagnesium bromide (3M in lether; 0.4mL) was added. The suspension was stirred for 30 min and allowed to warm to -10 °C. The mixture was quenched slowly over 10 min with saturated s NH4C| solution (10 mL). The mixture was diluted with saturated aqueous NH4C| solution (30 mL) and water (15 mL). The separated aqueous phase was extract with DCM (2x 75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2804, filtered off and concentrated under reduced pressure. The e was purified by column chouromatography [Si02, 40 g, heptane/ethyl acetate followed by 5% MeOH in EtOAc] providing yl-N-((S)—1-(4-(pyrimidinyloxy)phenyl)ethyl)propanesulfinamide (55 mg; purity ~87%) as an off-white solid. LCMS m/z 320.0 (M + H)+, Rt 0.69 min.
Step 4: Preparation of (S)(4-(pyrimidinyloxy)phenyl)ethanamine To 2-methyl-N-((S)—1-(4-(pyrimidinyloxy)phenyl)ethyl)propanesulfinamide (55 mg, 0.172 mmol) was added 4M HCI in dioxane (800 uL, 3.20 mmol) to give a white suspension. This resulting mixture was stirred at room temperature for ~35 min and concentrated under d pressure to provide crude (S)—1-(4-(pyrimidin y|oxy)pheny|)ethanamine (44 mg) as its HCI salt, which was used without further purification. LCMS m/z 217.1 (M + H)+, Rt 0.37 min.
Intermediate 209: ro(1,1-dif|uoroethyl)nicotinaldehyde Step 1: Preparation of ethyl 5,6-dichloronicotinate To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH (500 mL) at 20 °C was added chlorotrimethylsilane (132 mL, 1042 mmol). The reaction was stirred for 72 hours. The reaction e was then concentrated and diluted with EtOAc (500mL), and washed with saturated NaHCO3 (2x100mL) and brine (100mL). The organic was then dried (Na2804) and concentrated under d pressure to give final crude product (21.25 g). LCMS m/z 220.1 (M + H)+, Rt 0.94 min.
Step 2: Preparation of ethyl 6-acetylch|oronicotinate To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) and tetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) was added tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) and PdC|2(PPh3)2 (0.671 g, 0.956 mmol). The on was sealed, heated at 80 °C for 5 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20 °C, concentrated and d with EtOAc (200mL), and washed with water (50mL) and brine (50mL). The organic was then dried (Na2804) and concentrated to give crude ethyl 5-chloro(1- ethoxyvinyl)nicotinate. The residue was then dissolved in THF (100mL) and HCI (20mL, 3M in H20) was added. The reaction mixture was stirred at 20 °C for 5 hours, and ted NaHCO3 solution was added until pH=8. The mixture was then diluted with EtOAc (200mL) and water (50mL). The phases were separated and the aqueous layer was extracted with EtOAc (2x50mL). The ed organics was washed with brine (20mL), dried (Na2804) and concentrated to afford the desired product (3.56 g). LCMS m/z 228.5 (M + H)+, Rt 0.83 min.
Step 3: Preparation of ethyl ro(1,1-difluoroethyl)nicotinate To a solution of ethyl 6-acetylchloronicotinate (3.01 g, 13.22 mmol) in CHCI3 (7 mL) was added DAST (5.20 mL, 39.7 mmol) and ethanol (0.061 g, 1.32 mmol). The reaction was sealed, heated at 60 0C for 24 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20 °C, and added cautiously with cold concentrated NaHCO3 aqueous solution (50mL). The aqueous layer was extracted with DCM (2x100mL). The combined c was then dried (Na2804) and trated. The residue was purified via silica gel flash chromatography (0-20percent EtOAc-Hexanes) to afford the desired product as yellow oil (2.88 g). LCMS m/z 250.1 (M + H)+, Rt 0.99 min.
Step 4: Preparation of (5-chloro(1,1-difluoroethyl)pyridinyl)methanol To a solution of ethyl 5-chloro(1,1-dif|uoroethy|)nicotinate (2.68 g, 10.74 mmol) in EtZO (40mL) was added LiBH4 (0.351 g, 16.10 mmol), followed by dropwise addition of methanol (0.653 mL, 16.10 mmol). The reaction was refluxed at 40 °C for one hour. The on mixture was then cooled to 0 °C, and quenched with HCI (1M) until pH=2 for s layer. The phases were separated and the aqueous layer was extracted with DCM (3x50mL). The organic was then dried (Na2804) and concentrated under reduced pressure to give final crude product (2.12 g). LCMS m/z 208.0 (M + H)+, Rt 0.63 min.
Step 5: Preparation of 5-chloro(1,1-difluoroethyl)nicotinaldehyde To a solution of (5-chloro(1,1-dif|uoroethy|)pyridinyl)methano| (2.12 g, 10.21 mmol) in DCM (100 ml) was added PCC (3.30 g, 15.32 mmol). The reaction was stirred at 20 °C for 3 hours. A dark color suspension ed. LCMS showed clean conversion to the product. The reaction mixture was then filtered through a pad of celite, and washed with DCM (200mL). The filtrate was then concentrated to give crude product (1.78 g). LCMS m/z 224.0 (M + H2O + H)+, Rt 0.72 min.
Intermediate 210: 5-chloro(2,2,2-trifluoroethoxy)nicotinaldehyde Step 1: Preparation of ethyl 5-chloro(2,2,2-trifluoroethoxy)nicotinate To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and 2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at -730C was added NaHMDS (37.1 ml, 37.1 mmol).
The reaction was stirred at -73 °C for 30 minutes, then at 0 °C for 5 hours. The reaction was quenched with 30 mL saturated NH4C| solution. The reaction mixture was then poured into 50 mL brine and phases were separated. The aqueous layer was extracted with DCM (2x100mL). The combined organics were dried 4) and concentrated.
Silica gel chromatography with 100% heptane to 30% EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M + H)+, Rt 1.07 min.
Step 2: Preparation of (5-chloro(2,2,2-trifluoroethoxy)pyridinyl)methanol To a on of ethyl ro(2,2,2-trifluoroethoxy)nicotinate (7.51 g, 26.5 mmol) in Et20 (200mL) was added LiBH4 (0.865 g, 39.7 mmol), followed by drop wise addition of methanol (1.611 mi, 39.7 mmol). The on was refluxed at 40 °C for one hour. The reaction mixture was then cooled to 0 °C, and ed with HCI (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3x200mL). The c was then dried (Na2804) and concentrated under reduced pressure to give final crude product (6.31 g). LCMS m/z 242.1 (M + H)+, Rt 0.77 min.
Step 3: Preparation of 5-chloro(2,2,2-trifluoroethoxy)nicotinaldehyde To a solution of (5-chloro(2,2,2-trifluoroethoxy)pyridinyl)methanol (4.00 g, 16.56 mmol) in EtOAc (15 mL) was added manganese(lV) oxide (16.93 g, 166 mmol). The reaction was heated with microwave at 120 °C for 30 minutes. The mixture was then filtered through a pad of celite, and rinsed with EtOAc. The filtrated was concentrated to give crude product (3.38 g).
The intermediates in Table 4w were ed with procedures similar to those used to prepare Intermediate 210 and 192.
Table 4w. 211: (R)—N-((S)—1-(5-ch|oro MS m/z 325.2 (1,1-difluoroethyl)pyridin (M + H)+, Rt yl)ethyl)methylpropane—2- S 0.85 min. amide 212: ((S)—1-(5-ch|oro MS m/z 359.1 (2,2,2-trifluoroethoxy)pyridin (M + H)+, Rt yl)ethyl)—2-methylpropane s C 0.95 min. sulfinamide Intermediate 213 : (S)(2-((S)(4-(chloromethyl)phenyl)ethylamino)pyrimidin yl)isopropyloxazolidinone To a solution of (S)(2-((S)—1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone (71 mg, 0.2 mmol) in DCM (2 mL) was added methanesulfonyl chloride (27 mg, 0.24 mmol) and DIPEA (0.070 mL, 0.4 mmol). The solution was stirred for 16 h at room temperature then washed with water and brine. After separation, the organic phase was dried over NaZSO4, ed and concentrated. The crude product was used to next step without further purification.
MS m/z 373.4 (M - H).
Intermediate 214: tert-butyl (S)(4-((S)isopropy|oxooxazo|idin yl)pyrimidinylamino)ethy|)benzyl)-3,8-diazabicyc|o[4.2.0]octanecarboxylate Title compound was prepared as a white solid (64 mg, 58.1% yield), with procedures similar to those used to prepare Intermediate 128, but utilizing 4-((S)(4-((S)—4- isopropyloxooxazolidinyl)pyrimidinylamino)ethyl)benzaldehyde and tert-butyl 3,8- diazabicyclo[4.2.0]octane—8-carboxylate. 1H NMR (400 MHz, CDCI3) 5 8.17 (dd, J = 5.9, 0.9 Hz, 1H), 7.42 (d, J = 5.7 Hz, 1H), 7.28 - 7.23 (m, 4H), 5.39 (br s, 1H), 5.02 (br s, 1H), 4.62-4.59 (m, 1H), 4.28 (t, J = 8.7 Hz, 1H), 4.21 (dd, J = 9.0, 3.2 Hz, 2H), 3.89 (td, J = 7.7, 1.9 Hz, 1H), 3.54 - 3.50 (m, 2H), 3.03 (d, J = 12.2 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.54 — 2.40 (m, 2H), 2.10 (br s, 1H), 1.99 - 1.88 (m, 1H), 1.79 - 1.72 (m, 1H), 1.65 (br s, 1H), 1.52 (dd, J = 6.8, 1.9 Hz, 3H), 1.38 (t, J = 7.7 Hz, 9H), 0.71 (br s, 3H), 0.66 (br s, 3H). MS m/z 569.1 (M + H).
Intermediate 215: utyl 1-(4-((S)(4-((S)isopropyloxooxazolidin y|)pyrimidinylamino)ethyl)benzyl)piperidinylcarbamate WNUfiWL Title compound was prepared as a white solid (32 mg, 59% yield), with procedures similar to those used to prepare Intermediate 128, but utilizing 4-((S)(4-((S)—4- isopropyloxooxazolidinyl)pyrimidinylamino)ethyl)benzaldehyde and tert-butyl piperidinylcarbamate. MS m/z 539.4 (M + H).
Examples Example 1: (S)—5,5-dimethylphenyl(2-((S)—1-phenylethylamino)pyrimidin yl)oxazolidinone A solution of (2-chloropyrimidinyl)—5,5-dimethylphenyloxazolidinone (33.9 mg, 0.112 mmol) and (S)—(—)—1-phenylethanamine (0.15 mL, 1.2 mmol, 10 equiv) in DMSO (1 mL) was heated at 110 °C for 140 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) ed (S)—5,5-dimethylphenyl(2-((S)phenylethylamino)pyrimidinyl) oxazolidinone (37.0 mg, white solid) in 85% yield. 1H NMR (400 MHz, CD30D) 8 8.06 (d, J = 5.8 Hz, 1 H), 7.43 (d, J = 5.8 Hz, 1 H), 7.31 — 7.24 (m, 3 H), 7.19 — 7.11 (m, 5 H), 7.01 (br s 2 H), 5.48 (s, 1 H), 4.86 — 4.80 (m, 1 H), 1.65 (s, 3 H), 1.43 (d, J = 7.0 Hz, 3 H), 0.98 (s, 3 H); HRMS(B) m/z 389.1987 (M + H)+.
Alternative Procedure Example 113: (S)(2-((S)—1-(4-hydroxyphenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone A solution of (2-chloropyrimidinyl)isopropyloxazolidinone (42 mg, 0.17 mmol), (S)—4-(1-aminoethyl)phenol hydrochloride (107 mg, 0.616 mmol, 3.5 equiv) and iPr2Net (0.121 mL, 0.695 mmol, 4.0 equiv) in DMSO (1 mL) was heated at 110 0C for 3 h and at 130 °C for additional 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, ed and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 80%) provided (S)—3-(2-((S)—1-(4-hydroxyphenyl)ethylamino)pyrimidinyl)isopropyloxazolidinone (3 mg) in 5 % yield. 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = .8 Hz, 1 H), 7.12 (d, J 8.1 Hz, 2 H), 6.72 — 6.68 (m, 2 H), 4.95 (q, J = 6.9 Hz, 1 H), 4.69 — 4.65 (m, 1 H), 4.35 — 4.28 (m, 2 H), 1.47 (d, J = 7.1 Hz, 3 H), 0.75 (br s, 3 H), 0.62 (br s, 3 H); ) m/z 343.1776 (M + H)+.
The compounds in Table 5 were ed using methods similar to those described for the preparation of Examples 1 and 113.
WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 Table 6. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 5.
Example: Name 1H NMR (400 MHz, CD30D) 8 ppm (other LCMS solvents described 1: 5-dimethyl 8.06 (d, J = 5.8 Hz, 1 H), 7.43 (d, J = 5.8 HRMS(B) phenyl(2-((S)—1- Hz, 1 H), 7.31 — 7.24 (m, 3 H), 7.19 — 7.11 m/z ethylamino)pyrimidi (m, 5 H), 7.01 (br s 2 H), 5.48 (s, 1 H), 4.86 389.1987 nyl)oxazolidinone — 4.80 (m, 1 H), 1.65 (s, 3 H), 1.43 (d, J = (M + H)+ 7.0 Hz, 3 H , 0.98 s, 3 H 2: 3-(2-(1- 8.06 (d, J = 6.1 Hz, 1 H), 7.37 — 7.26 (m, 5 HRMS(B) phenylethylamino)pyrimidi H), 7.22 — 7.15 (m, 1 H), 5.04 (q, J = 6.9 m/z nyl)oxazolidinone Hz, 1 H), 4.43 (sxt, J = 8.2 Hz, 2 H), 4.17 75 (td, J = 9.8, 7.1 Hz, 1 H), 3.92 (br s, 1 H), M+ 1.50 d, J = 7.1 Hz, 3 H 3: isopropyl(2- 8.12 (d, J = 5.6 Hz, 1 H), 7.34 — 7.26 (m, 5 HRMS(B) ((S) H), 7.22 — 7.13 (m, 1 H), 5.04 (q, J = 7.1 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.64 (br s, 1 H), 4.34 — 4.26 (m, 2 326.1745 nyl)oxazolidinone H), 1.85 (br s, 1 H), 1.50 (d, J = 7.1 Hz, 3 M+ , 0.70 brs, 3 H , 0.57 brs, 3 H 4: (S)isopropyl(2- 8.10 (d, J = 5.8 Hz, 1 H), 7.35 — 7.27 (m, 5 HRMS(B) ((R) H), 7.23 — 7.15 (m, 1 H), 4.96 (q, J = 6.9 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.44 (br s, 1 H), 4.34 — 4.23 (m, 2 326.1746 nyl)oxazolidinone H), 2.72 — 2.58 (m, 1 H), 1.51 (d, J = 6.6 M+ Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.1 Hz, 3 H : (S)—4-phenyl(2-((S)- 8.07 (d, J = 5.6 Hz, 1 H), 7.38 (d, J = 5.6 HRMS(B) 1- Hz, 1 H), 7.28 — 7.05 (m, 10 H), 5.84 (dd, J m/z phenylethylamino)pyrimidi = 8.6, 3.5 Hz, 2 H), 4.88 (q, J = 6.8 Hz, 1 361.1666 nyl)oxazolidinone H), 4.83 — 4.79 (m, 1 H), 4.24 (dd, J = 8.6, (M + H)+ 1.44 , d,J :68 Hz, 3 H 6: (S)—4-phenyl(2-((R)— 8.08 (d, J = 5.8 Hz, 1 H), 7.43 — 7.18 (m, HRMS(B) 1- 11H,5.55 brs,1H,4.74 t,J=8.6Hz,1 m/z H), 4.63 (brs, 1 H), 4.18 (dd, J = 8.3, 3.8 n | oxazolidinone , 1.19 d, J = 6.7 Hz, 3 H M+ 7: (S)—3-(2- 8.06 (d, J = 6.1 Hz, 1 H), 7.39 — 7.28 (m, 6 HRMS(B) (cyclopentylamino)pyrimidi H), 5.80 (dd, J = 8.8, 3.8 Hz, 1 H), 4.83 — m/z ny|) 4.80 (m, 1 H), 4.20 (dd, J = 8.6, 4.0 Hz, 1 325.1671 phenyloxazolidinone H), 3.79 (br m, 1 H), 1.90 — 1.99 (m, 1 H), (M + H)+ 1.72— 1.53 m, 4 H , 1.49— 1.35 m, 3 H 8: (S)—3-(2- 8.10 (d, J = 5.6 Hz, 1 H), 7.44 (d, J = 5.6 HRMS(B) (cyclopropylamino)pyrimid Hz, 1 H), 7.36 — 7.26 (m, 5 H), 5.86 (dd, J m/z iny|) = 8.6, 3.5 Hz, 1 H), 4.83 — 4.80 (m, 1 H), 297.1356 oxazolidinone 4.26 (dd, J = 8.6, 3.5 Hz, 1 H), 2.40 (br s, 1 (M + H)+ H), 0.64 — 0.71 (m, 1 H), 0.54 (br s, 1 H), 0.44—0.37 m, 1 H , 0.25 br s, 1 H 9: (S)—3-(2- 8.06 (d, J = 6.1 Hz, 1 H), 7.38 — 7.27 (m, 6 HRMS(B) (cycloheptylamino)pyrimidi H), 5.82 (dd, J = 8.6, 3.5 Hz, 1 H), 4.83 — m/z ny|) 4.80 (m, 1 H), 4.21 (dd, J = 8.6, 3.5 Hz, 1 61 phenyloxazolidinone H), 3.57 (br s, 1 H), 1.90 (br s, 1 H), 1.69 — (M + H)+ . ,1.32—1.18 m,3H : (R)pheny|—3-(2-((S)— 8.08 (d, J = 5.8 Hz, 1 H), 7.43 — 7.18 (m, HRMS(B) 1- 11 H), 5.54 (br s, 1 H), 4.74 (t, J = 8.6 Hz, m/z phenylethylamino)pyrimidi 1 H), 4.62 (br s, 1 H), 4.18 (dd, J = 8.8, 3.8 361.1712 n | idinone , 1.19 d, J = 6.6 Hz, 3 H M + H + 11: (R)pheny|—3-(2-((R)— 8.07 (d, J = 5.8 Hz, 1 H), 7.38 (d, J = 5.8 ) 1- Hz, 1 H), 7.28 — 7.05 (m, 10 H), 5.84 (dd, J m/z phenylethylamino)pyrimidi = 8.3, 3.3 Hz, 1 H), 4.88 (q, J = 6.9 Hz, 1 361.1661 ny|)oxazo|idinone H), 4.82 — 4.78 (m, 1 H), 4.24 (dd, J = 8.6, (M + H)+ 1.44 , d,J :69 Hz, 3 H 12: (S)—4-isopropy|—3-(2- 8.11 (d, J = 5.6 Hz, 1 H), 7.33 — 7.26 (m, 5 HRMS(B) ((S) H), 7.22 — 7.15 (m, 1 H), 4.83 — 4.79 (m, 1 m/z phenylpropylamino)pyrimi H), 4.68 (br s, 1 H), 4.36 — 4.28 (m, 2 H), 341.1974 dinyl)oxazolidinone 1.84 (quin, J = 7.3 Hz, 2 H), 0.99 (t, J = 7.3 (M + H)+ Hz, 3 H , 0.76 brs, 3 H , 0.59 brs, 3 H 13: isopropy|—3-(2- 8.09 (d, J = 5.8 Hz, 1 H), 7.34 — 7.27 (m, 5 HRMS(B) ((R) H), 7.24 — 7.16 (m, 1 H), 4.74 (t, J = 6.8 m/z phenylpropylamino)pyrimi Hz, 1 H), 4.52 (br s, 1 H), 4.36 — 4.26 (m, 2 341.1976 diny|)oxazo|idinone H), 2.66 (td, J = 6.9, 3.8 Hz, 1 H), 1.95 — (M + H)+ 1.75 (m, 2 H), 1.02 (d, J = 7.1 Hz, 3 H), 0.96 (t, J = 7.3 Hz, 3 H), 0.86 (d, J = 7.1 14: provided (S)—4- 8.09 (d, J = 5.8 Hz, 1 H), 7.32 — 7.23 (m, 3 HRMS(B) benzhydryI(2-((S) H), 7.20 — 7.16 (br m, 6 H), 7.00 (br s, 5 m/z phenylethylamino)pyrimidi H), 6.72 (br s, 2 H), 5.76 — 5.68 (m, 1 H), 451.2126 )oxazo|idinone 5.04 (q, J = 7.1 Hz, 1 H), 4.59 (t, J = 8.8 (M + H)+ Hz, 1 H), 4.50 (br s, 1H), 4.47 (dd, J = 9.1, 1.44 , d, J =7.1 Hz, 3 H : (4S,5R)—4-methy|—5- 8.12 (d, J = 5.8 Hz, 1 H), 7.45 — 7.30 (m, 8 HRMS(B) phenyI(2-((S) H), 7.20 (t, J = 7.6 Hz, 2 H), 7.10 — 7.07 m/z phenylethylamino)pyrimidi (m, 1 H), 5.80 (d, J = 7.1 Hz, 1 H), 5.10 — 375.1823 ny|)oxazo|idinone 4.92 (m, 2 H), 1.49 (d, J = 7.0 Hz, 3 H), (M + H)+ 0.37 br s, 3 H 16: 3-(2- 8.07 (d, J = 5.7 Hz, 1 H), 7.32 (d, J = 5.8 HRMS(B) (cyclopentylamino)pyrimidi Hz, 1 H),4.48 (t, J = 8.1 Hz, 2 H), 4.22 — m/z ny|)oxazo|idinone 4.16 (m, 3 H), 2.02 (dq, J = 12, 6.1 Hz, 2 248.1275 H), 1.70 — 1.80 (m, 2 H), 1.67 — 1.47 (m, 4 M+ 2012/055133 17: (S)—4-benzyI(2- 8.13 (d, J = 5.8 Hz, 1 H), 7.35 — 7.21 (m, 6 HRMS(B) (cyclopentylamino)pyrimidi H), 5.14 — 5.04 (m, 1 H), 4.36 (t, J = 8.4 m/z ny|)oxazo|idinone Hz, 1 H), 4.33 — 4.24 (m, 2 H), 3.37 — 3.33 338.1749 (m, 1 H), 3.06 (dd, J = 13, 8.3 Hz, 1 H), M+ 2.11 — 1.98 (m, 2 H), 1.86 — 1.71 (m, 2 H), 1.70— 1.53 m, 4 H 18: (R)benzy|—3-(2- 8.13 (d, J = 5.6 Hz, 1 H), 7.35 — 7.21 (m, 6 HRMS(B) (cyclopentylamino)pyrimidi H), 5.14 — 5.05 (m, 1 H), 4.36 (t, J = 8.5 m/z )oxazo|idinone Hz, 1 H), 4.32 — 4.26 (m, 2 H), 3.37 — 3.33 48 (m, 1 H), 3.06 (dd, J =13,8.3 Hz, 1 H), M+ 2.13 — 1.99 (m, 2 H), 1.85 — 1.71 (m, 2 H), 1.70— 1.51 m, 4 H 19: (4R,5S)—4-methy|—5- 8.11 (d, J = 5.8 Hz, 1 H), 7.48 — 7.28 (m, HRMS(B) phenyI(2-((S) 10 H), 7.24 — 7.21 (m, 1 H), 5.70 (d, J = m/z phenylethylamino)pyrimidi 6.8 Hz, 1 H), 4.96 — 4.90 (m, 1 H), 4.65 (br 375.1824 ny|)oxazo|idinone s, 1 H)1.49 (d, J = 7.1 Hz, 3 H), 0.97 (d, J (M + H)+ : (S)—4-benzhydry|—3-(2- 8.13 (d, J = 5.8 Hz, 1 H), 7.47 — 7.40 (m, 2 HRMS(B) ((R) H), 7.35 — 7.22 (m, 5 H), 7.19 — 7.10 (m, 5 m/z phenylethylamino)pyrimidi H), 7.01 — 6.99 (m, 2 H), 6.89 (br s, 2 H), 451.2134 )oxazo|idinone 5.26 (br s, 1 H), 5.09 (br s, 1 H), 4.76 (br s, (M + H)+ 1 H), 4.54 — 4.44 (m, 2 H), 1.37 (d, J = 7.1 Hz, 3 H 21: (R)isopropy|—3-(2- 8.10 (d, J = 5.8 Hz, 1 H), 7.35 — 7.27 (m, 5 HRMS(B) ((S) H), 7.20 — 7.17 (m, 1 H), 4.96 (q, J = 6.7 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.44 (br s, 1 H), 4.32 (dd, J = 9.1, 327.1824 ny|)oxazo|idinone 2.5 Hz, 1 H), 4.25 (t, J = 8.6 Hz, 1 H), 2.65 (M + H)+ (dtd, J = 14, 7.0, 3.5 Hz, 1 H), 1.51 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 d,J=7.1Hz,3H 22: (R)isopropy|—3-(2- 8.12 (d, J = 5.8 Hz, 1 H), 7.37 — 7.25 (m, 5 HRMS(B) ((R) H), 7.19 — 7.16 (m, 1H), 5.04 (q, J = 6.9 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.64 (br s, 1 H), 4.35 — 4.26 (m, 2 327.1821 ny|)oxazo|idinone H), 1.88 (br s, 1 H), 1.50 (d, J = 6.6 Hz, 3 (M + H)+ , 0.70 brs, 3 H , 0.57 brs, 3 H 23: (S)—4-isopropy|—5,5- 8.13 (d, J = 5.8 Hz, 1 H), 7.35 — 7.26 (m, 5 HRMS(B) dimethyI(2-((S) H), 7.19 — 7.16 (m, 1H), 5.08 — 5.03 (m, 1 m/z phenylethylamino)pyrimidi H), 4.45 (br s, 1 H), 1.99 (br s, 1 H), 1.52 355.2132 ny|)oxazo|idinone (s, 3 H), 1.50 (d, J = 7.1 Hz, 3 H), 1.41 (s, (M + H)+ 3 H ,0.73 brs, 3 H ,0.58 brs, 3 H 24: isopropy|—5,5- 8.10 (d, J = 5.8 Hz, 1 H), 7.34 — 7.25 (m, 5 HRMS(B) dimethyI(2-((R) H), 7.18 — 7.15 (m, 1 H), 4.93 (br s, 1 H), m/z phenylethylamino)pyrimidi 4.32 (br s, 1 H), 2.25 (td, J = 6.8, 3.5 Hz, 1 355.2128 ny|)oxazo|idinone H), 1.50 (d, J = 7.1 Hz, 3 H), 1.49 (s, 3 H), (M + H)+ 1.09 (br s, 3 H), 1.03 (d, J = 7.1 Hz, 3 H), 0.95 d, J = 7.1 Hz, 3 H : (4R,5S)—4-methy|—5- 8.12 (d, J = 5.8 Hz, 1 H), 7.45 — 7.30 (m, 8 HRMS(B) phenyI(2-((R) H), 7.20 (t, J = 7.3 Hz, 2 H), 7.10 — 7.06 m/z phenylethylamino)pyrimidi (m, 1 H), 5.80 (d, J = 7.0 Hz, 1 H), 5.01 — 23 ny|)oxazo|idinone 4.94 (m, 2 H), 1.49 (d, J 7.0 Hz, 3 H), 0.30 (M + H)+ 26: (4S,5R)—4-methy|—5- 8.10 (d, J = 5.8 Hz, 1 H), 7.48 — 7.28 (m, HRMS(B) phenyI(2-((R) 10 H), 7.24 — 7.20 (m, 1 H), 5.69 (br s, 1 m/z phenylethylamino)pyrimidi H), 5.01 — 4.93 (m, 1 H), 4.59 (br s, 1 375.1819 n | oxazolidinone H 1.49 d, J = 7.1 Hz, 3 H , 0.96 d, J = 6.5 M + H + 2012/055133 27: (S)—5,5-dimethy|—4— 8 8.08 (d, J = 5.9 Hz, 1 H), 7.44 — 7.39 (m, ) phenyl-3—(2—((R)—1 - 3 H), 7.36 — 7.29 (m, 5 H), 7.22 — 7.17 (m, m/z phenylethylamino)pyrimidi 3 H), 5.16 (brs, 1 H), 4.55 (brs, 1 H), 1.49 74 nyl)oxazo|idin-2—one (s, 3 H), 1.18 (d, J = 6.8 Hz, 3 H), 0.96 (s, (M+HY 28: (S)—3—(2—((S)—2,3— 8.16 (d, J = 5.8 Hz, 1 H), 7.41 (d, J = 5.9 HRMS(B) dihydro—1 H-inden Hz, 1 H), 7.25 — 7.13 (m, 4 H), 5.48 (t, J = m/z y|amino)pyrimidin-4—y|) 7.8 Hz, 1 H), 4.79 — 4.68 (m, 1 H), 4.36 (d, 339.1825 pyloxazolidinone J = 6.1 Hz, 2 H), 3.01 (ddd, J = 16, 8.6, 3.0 (M+HY Hz, 1 H), 2.94 — 2.81 (m, 1 H), 2.66 — 2.54 (m, 2 H), 2.01 — 1.92 (m, 1 H), 0.86 (d, J = 6.9 Hz, 3 H , 0.85 d, J = 6.9 Hz, 3 H 29: (S)—3—(2-((R)—2,3— 8.15 (d, J = 5.8 Hz, 1 H), 7.41 (d, J = 5.8 HRMS(B) dihydro—1 H-inden Hz, 1 H), 7.29 — 7.15 (m, 4 H), 5.48 (t, J = m/z y|amino)pyrimidin-4—y|) 7.6 Hz, 1 H), 4.83 — 4.79 (m, 1 H), 4.41 — 339.1830 pyloxazolidinone 4.36 (m, 2 H), 3.03 (ddd, J = 16, 8.8, 3.3 (M+HY Hz, 1 H), 2.86 (dt, J = 16, 8.0 Hz, 1 H), 2.64 — 2.50 (m, 2 H), 2.00 — 1.91 (m, 1 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.1 : (4R,5S)—4,5-dipheny|— 8.12 (d, J = 5.8 Hz, 1 H), 7.48 (d, J = 5.8 HRMS(B) 3-(2-((S) Hz, 1 H), 7.33 — 7.20 (m, 5 H), 7.13 — 7.08 m/z phenylethylamino)pyrimidi (m, 6 H), 7.03 — 7.00 (m, 2 H), 6.88 — 6.86 437.1982 nyl)oxazo|idin-2—one (m, 2 H), 5.99 (d, J = 8.0 Hz, 1 H), 5.76 (br (M+HY s,1H,4.53 brs,1H,1.11brs,3H 31: (S)—4—isobuty|—3—(2— 8.11 (d, J = 5.8 Hz, 1 H), 7.36 — 7.28 (m, 5 HRMS(B) «$4- H), 7.21 — 7.18 (m, 1 H), 5.18 (q, J = 6.9 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.83 — 4.79 (m, 1 H), 4.46 (t, J = 341.1974 nyl)oxazo|idin-2—one 8.5 Hz, 1 H), 4.23 (dd, J = 9.0, 3.0 Hz, 1 (M+HY H), 1.57 (br s, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.33 (br s, 1 H), 0.82 (br s, 3 H), 0.73 32: (S)—4—isobuty|—3—(2— 8.09 (d, J = 5.8 Hz, 1 H), 7.36 — 7.27 (m, 5 HRMS(B) «RH- H), 7.21 — 7.18 (m, 1 H), 5.16 (q, J = 7.0 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.69 (brs, 1 H), 4.42 (t, J = 8.3 341.1972 nyl)oxazo|idin-2—one Hz, 1 H), 4.24 (dd, J = 8.8, 2.8 Hz, 1 H), (M+HY 1.92 — 1.86 (m, 1 H), 1.80 — 1.70 (m, 1 H), 1.58 (ddd, J =13, 10, 4.8 Hz, 1 H), 1.52 (d, J = 7.0 Hz, 3 H), 1.07 (d, J = 6.5 Hz, 3 H), 0.98 d, J = 6.5 Hz, 3 H 33: (4S)isopropy|—3—(2— 8.49 — 8.48 (m, 1 H), 8.13 (dd, J = 10, 5.8 HRMS(B) (1 -(pyridin-2— Hz, 1 H), 7.75 (td, J = 7.7, 1.8 Hz, 1 H), m/z y|)ethy|amino)pyrimidin 7.43 — 7.36 (m, 2 H), 7.29 — 7.23 (m, 1 H), 328.1762 y|)oxazolidin-2—one 5.08 — 4.99 (m, 1 H), 4.60 (br s, 0.5 H), (M+HY 4.34 — 4.22 (m, 2.5 H), 2.63 — 2.56 (m, 0.5 H), 1.55 (d, J = 7.0 Hz, 1.5 H), 1.54 (d, J = 7.0 Hz, 1.5 H), 1.53 (br s, 0.5 H), 0.97 (d, J = 7.1 Hz, 1.5 H), 0.83 (d, J = 7.1 Hz, 1.5 , 0.65 brs,1.5H,0.55 brs,1.5H 34: (4S)isopropy|—3—(2— 8.45 — 8.43 (m, 2 H), 8.14 (dd, J = 12, 5.6 HRMS(B) (1 -(pyridin-4— Hz, 1 H), 7.43 — 7.37 (m, 2 H), 5.05 (q, J = m/z y|)ethy|amino)pyrimidin 7.1 Hz, 0.5 H), 4.99 — 4.95 (br m, 0.5 H), 328.1772 y|)oxazolidin-2—one 4.59 (br s, 0.5 H), 4.33 — 4.26 (m, 2.5 H), (M+HY 2.64 — 2.59 m, 0.5 H , 1.53 d, J = 7.1 Hz, 35H)097«LJ=71H;15H)084@, J=71HL15HLO62®ra15H)057 : (S)—4-isopropyI(2- 8.19 — 8.16 (m, 2 H), 7.88 (d, J = 8.1 Hz,1 HRMS(B) ((S)(naphthalen H), 7.72 (d, J = 8.1 Hz, 1 H), 7.56 — 7.45 m/z y|)ethy|amino)pyrimidin (m, 3 H), 7.40 — 7.32 (m, 2 H), 5.80 (q, J = 377.1969 y|)oxazolidinone 6.6 Hz, 1 H), 4.32 (brs, 1 H), 4.17 —4.13 (M+HY (m, 1 H), 4.05 (brs, 1 H), 1.64 (d, J = 7.1 Hz, 3 H), 1.15 (br s, 1 H), 0.23 (br s, 3 H), - 0.31 br s, 3 H 36: (S)—4-isopropyI(2- 8.09 (d, J = 5.6 Hz, 1 H), 7.33 (d, J = 6.1 HRMS(B) «RH44 Hz, 1 H), 7.28 — 7.24 (m, 2 H), 6.87 — 6.83 m/z methoxyphenyl)ethylamin (m, 2 H), 4.93 (q, J = 6.9 Hz, 1 H), 4.52 (br 357.1928 o)pyrimidin s, 1 H), 4.35 — 4.26 (m, 2 H), 3.75 (s, 3 H), (M+HY zolidinone 2.65 (ddt, J = 10, 6.9, 3.5, 1 H), 1.48 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.83 d, J = 6.8 Hz, 3 H 37: (4S,5R)—4,5-dipheny|— 8.10 (d, J = 5.8 Hz, 1 H), 7.50 (d, J = 5.8 HRMS(B) 3-(2-((S) Hz, 1 H), 7.12 — 7.09 (m, 6 H), 7.06 — 7.03 m/z phenylethylamino)pyrimidi (m, 2 H), 7.01 — 6.97 (m, 5 H), 6.83 — 6.81 437.1984 ny|)oxazo|idinone (m, 2 H), 6.10 (s, 2 H), 4.86 — 4.81 (br m, 1 (M+HY 1.42 , d,J :65 Hz, 3 H 38: (4S,5R)—4,5-dipheny|— 8.11 — 8.09 (m, 1 H), 7.47 (d, J = 5.8 Hz,1 HRMS(B) 3-(2-((R) H), 7.32 — 7.20 (m, 5 H), 7.12 — 7.07 (m, 6 m/z phenylethylamino)pyrimidi H), 7.02 — 6.99 (m, 2 H), 6.86 (d, J = 6.5 437.1970 ny|)oxazo|idinone Hz, 2 H), 5.98 — 5.93 (br m, 1 H), 5.75 (br (M+HY s, 1 H H , 4.53 brs,1H,1.11brs,3 39: (4R,5S)—4,5-dipheny|— 8.09 (d, J = 5.9 Hz, 1 H), 7.50 (d, J = 5.8 HRMS(B) 3-(2-((R) Hz, 1 H), 7.11 — 7.09 (m, 6 H), 7.05 — 7.03 m/z phenylethylamino)pyrimidi (m, 2 H), 7.00 — 6.95 (m, 5 H), 6.82 — 6.80 437.1975 )oxazo|idinone (m, 2 H), 6.09 (s, 2 H), 4.87 — 4.81 (br m, 1 (M+HY 1.41 , d,J =7.0 Hz, 3 H 40: (S)—4-isopropy|—3-(2- 8.16 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 5.8 HRMS(B) ((R)(naphtha|en Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.56 — m/z y|)ethy|amino)pyrimidin 7.45 (m, 3 H), 7.42 — 7.38 (m, 1 H), 7.33 377.1981 y|)oxazolidinone (d, J = 5.8 Hz, 1 H), 5.81 (q, J = 6.6 Hz, 1 (M+HY H), 4.15 (brs, 1 H), 4.03 (brs, 1 H), 2.56 (td, J = 7.1, 3.5 Hz, 1 H), 1.65 (d, J = 7.1 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H), 0.74 (br 41: (S)—4-isopropy|—3-(2- 8H(¢J=58H;1H)733@J=59 HRMS(B) «$444 HL1H)722wHJ=86HL2H)685— m/z methoxyphenyl)ethylamin 682mL2HL498mflJ=69HL1HL 357.1922 midin 467—463mL1H)434—427mL2H) (M+HY y|)oxazolidinone 375(S,3FD,194(brs,1H) J= 7A Hz,3FD,073(brs,3FD,061(brs,3 42: (S)—4-isopropy|—3-(2- 9.11 (s, 1 H), 9.03 (s, 2 H), 8.14 (d, J = 5.8 HRMS(B) ((S)—1-(4-(pyrimidin Hz, 1 H), 7.69 — 7.66 (m, 2 H), 7.52 (d, J = m/z y|)phenyl)ethylamino)pyri 8.1 Hz, 2 H), 7.35 (d, J = 5.8 Hz, 1 H), 5.11 405.2035 4-y|)oxazo|idin (q, J = 6.9 Hz, 1 H), 4.65 (br s, 1 H), 4.35 — (M+HY one 4.26 (m, 2 H), 1.80 (brs, 1 H), 1.55 (d, J = 7.1 Hz, 3 H), 0.66 (br s, 3 H), 0.55 (br s, 3 43: S iSOpr0p I 2- 8.10 d, J = 5.9 HZ, 1 H — 7.75 , 7.80 m, 4 HRMS B ((R)(naphtha|en H), 7.51 — 7.48 (m, 1 H), 7.43 — 7.36 (m, 2 m/z y|)ethy|amino)pyrimidin H), 7.32 (d, J = 5.8 Hz, 1 H), 5.15 — 5.07 84 y|)oxazolidinone (m, 1 H), 4.36 (br s, 1 H), 4.24 (dd, J = 9.1, (M + H)+ 2.5 Hz, 1 H), 4.14 — 4.06 (br m, 1 H), 2.67 (dtd, J = 14, 6.9, 3.5 Hz, 1 H), 1.60 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.83 d,J=7.1Hz,3H 44: (R)(2-((S)—1-(4- 8.09 — 8.07 (m, 1 H), 7.41 — 7.18 (m, 8 H), HRMS(B) fluoropheny|)ethy|amino)p 7.12 — 7.07 (m, 2 H), 5.21 (s, 1 H), 4.99 — m/z yrimidiny|)-5,5- 4.93 (m, 1 H), 1.50 (s, 3 H), 1.24 (d, J = 407.188 dimethyI 7.1 Hz, 3 H), 0.98 (s, 3 H) (M + H)+ phen onazolidinone 45: (R)isobutyI(2- 8.10 (d, J = 5.8 Hz, 1 H), 7.36 — 7.27 (m, 5 HRMS(B) ((R) H), 7.22 — 7.17 (m, 1 H), 5.18 (q, J = 6.9 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.82 — 4.78 (m, 1 H), 4.46 (t, J = 341.1967 )oxazo|idinone 8.6 Hz, 1 H), 4.22 (dd, J = 8.6, 3.0 Hz, 1 (M + H)+ H), 1.62 — 1.54 (m, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.36 — 1.30 (m, 1 H), 0.82 (br s, 3 , 0.73 brs, 3 H 46: )—5-methy|—4- 8.05 (d, J = 5.8 Hz, 1 H), 7.42 (d, J = 5.8 HRMS(B) phenyI(2-((S) Hz, 1 H), 7.31 — 7.26 (m, 3 H), 7.19 — 7.11 m/z phenylethylamino)pyrimidi (m, 5 H), 7.02 (br s, 2 H), 5.80 (d, J = 7.5 375.1828 ny|)oxazo|idinone Hz, 1 H), 5.11 — 5.04 (m, 1 H), 4.85 (q, J = (M + H)+ 6.7 Hz, 1 H), 1.44 (d, J = 7.0 Hz, 3 H), 0.97 d,J=6.5Hz,3H 47: (4S,5R)—5-methy|—4- 8.06 (d, J = 5.8 Hz, 1 H), 7.43 — 7.40 (m, 3 HRMS(B) phenyI(2-((R) H), 7.37 — 7.30 (m, 5 H), 7.23 — 7.17 (m, 3 m/z phenylethylamino)pyrimidi H), 5.51 (br d, J = 7.1 Hz, 1 H), 4.99 (quin, 375.1819 ny|)oxazo|idinone J = 6.8 Hz, 1 H), 4.63 (br s, 1 H), 1.16 (br (M + H)+ d, J = 6.3 Hz, 3 H), 0.95 (d, J = 6.5 Hz, 3 48: (S)—4-benzy|—5,5- (CDCI3) 8.18 (d, J = 5.7 Hz, 1 H), 7.43 (d, J HRMS(B) dimethyI(2-((S) = 5.7 Hz, 1 H), 7.31 — 7.17 (m, 10 H), 5.34 m/z phenylethylamino)pyrimidi (br s, 1 H), 5.14 (quin, J = 7.0 Hz, 1 H), 403.2133 ny|)oxazo|idinone 4.85 (dd, J = 10, 3.5 Hz, 1 H), 3.22 (br d, J (M + H)+ =14 Hz, 1 H), 2.72 (br s, 1 H), 1.57 (d, J = 6.5Hz,3H,1.42 s,3H,1.33 s,3H 49: (R)isobutyI(2- 8.09 (d, J = 6.1 Hz, 1 H), 7.36 — 7.27 (m, 5 HRMS(B) - H), 7.21 — 7.17 (m, 1 H), 5.16 (q, J = 7.1 m/z phenylethylamino)pyrimidi Hz, 1 H), 4.69 (t, J = 8.6 Hz, 1 H), 4.41 (t, J 341.1973 ny|)oxazo|idinone = 8.3 Hz, 1 H), 4.23 (dd, J = 8.6, 3.0 Hz, 1 (M + H)+ H), 1.92 — 1.86 (m, 1 H), 1.79 — 1.69 (m, 1 H), 1.57 (ddd, J =13, 10, 4.8 Hz, 1 H), 1.52 (d, J = 7.1 Hz, 3 H), 1.07 (d, J = 6.6 0.98 d,J=6.6Hz,3H 50: (S)—4-isopropy|—3-(2- 8.15 (d, J = 5.7 Hz, 1 H), 7.81 — 7.73 (m, 4 HRMS(B) -(naphthalen H), 7.49 — 7.38 (m, 3 H), 7.33 (d, J = 5.8 m/z y|)ethy|amino)pyrimidin Hz, 1 H), 5.18 (q, J = 7.1 Hz, 1 H), 4.57 (br 377.1979 y|)oxazolidinone s, 1 H), 4.30 — 4.25 (m, 1 H), 4.20 (br s, 1 (M + H)+ H), 1.60 (d, J = 7.1 Hz, 3 H), 1.59 (br s,1 , 0.34 brs, 6 H 51: (S)—4-isopropy|—3-(2- 8.08 (d, J = 5.6 Hz, 1 H), 7.32 (d, J = 5.6 HRMS(B) ((R)p- Hz, 1 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.10 (d, m/z tolylethylamino)pyrimidin- J = 8.1 Hz, 2 H), 4.95 — 4.90 (m, 1 H), 4.48 341.1972 4- onazolidinone br s, 1 H , 4.32 dd, J 9.1, 3.0 Hz, 1 H M + H + 4.25 (t, J = 8.8 Hz, 1 H), 2.55 (dtd, J =14, 7.1, 3.5 Hz, 1 H), 2.28 (s, 3 H), 1.48 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.84 d,J=7.1Hz,3H 52: (S)—4-benzyI-5,5- ) 8.17 (d, J = 5.7 Hz, 1 H), 7.44 (d, J HRMS(B) dimethyI(2-((R) = 5.7 Hz, 1 H), 7.38 — 7.21 (m, 10 H), 5.32 m/z phenylethylamino)pyrimidi (br s, 1 H), 5.02 (br s, 1 H), 4.59 — 4.58 (br 403.2133 ny|)oxazo|idinone m, 1 H), 3.34 (dd, J = 15, 4.0 Hz, 1 H), (M+HY 2.93 (dd, J = 15, 9.5 Hz, 1 H), 1.51 (d, J = ,1.35 s,3H,1.29 s,3H 53: (S)—3-(2-((S)—1 - (CDCI3) 8.55 — 8.53 (br m, 2 H), 8.18 (d, J HRMS(B) ethylamino)pyrimidi = 5.7 Hz, 1 H), 7.48 (d, J = 5.7 Hz, 1 H), m/z ny|)(pyridin 7.45 — 7.34 (m, 1 H), 7.30 — 7.15 (m, 5 H), 362.1620 y|)oxazo|idinone 5.77 (dd, J = 8.8, 3.8 Hz, 1 H), 5.25 (br s, 1 (M+HY H), 4.83 (br s, 1 H), 4.81 (t, J = 8.8 Hz, 1 H), 4.31 (dd, J = 8.8, 3.8 Hz, 1 H), 1.51 (d, J = 5.8 Hz, 3 H 54: 4-(4-methoxypheny|)- (CDCI3) 8.05 (d, J = 5.7 Hz, 1 H), 7.55 — HRMS(B) ,5-dimethyI(2-((S) 7.52 (m, 1 H), 7.37 — 7.20 (m, 4 H), 7.13 — m/z phenylethylamino)pyrimidi 5.99 (m, 3 H), 5.91 (d, J = 8.0 Hz, 1 H), 419.2093 ny|)oxazo|idinone 5.78 (d, J = 8.0 Hz, 1 H), 5.87 (br s, 0.5 H), (M+HY .57 (br s, 0.5 H), 5.01 (br s, 0.5 H), 4.82 (br s, 0.5 H), 4.54 (br s, 0.5 H), 3.83 (s, 1.5 H), 3.78 (s, 1.5 H), 3.35 (br s, 0.5 H), 1.55 (s, 1.5 H), 1.51 (d, J = 5.9 Hz, 1.5 H), 1.49 (s, 1.5 H), 1.29 — 1.27 (m, 1.5 H), 1.04 (s, 1.5H , 1.00 s,1.5H 55: (2- 8.08 (d, J = 5.8 Hz, 1 H), 7.41 (d, J = 5.8 HRMS(B) lamino)pyrimidin Hz, 1 H), 7.30 — 7.17 (m, 8 H), 7.09 (br d, J m/z y|)pheny|oxazo|idin = 7.1 Hz, 2 H), 5.59 (br dd, J =8.1, 3.0 Hz, 347.1512 one 1 H), 4.75 (t, J = 8.8 Hz, 1 H), 4.28 (dd, J = (M+HY 44, 15 Hz, 2 H), 4.19 (dd, J = 8.8, 3.8 Hz,1 56: (S)—3-(2- 8.10 (d, J = 5.7 Hz, 1 H), 7.42 (d, J = 5.9 HRMS(B) (benzylamino)pyrimidin Hz, 1 H), 7.31 — 7.15 (m, 8 H), 7.09 (br d, J m/z y|)pheny|oxazo|idin = 7.1 Hz, 2 H), 5.71 (br m, 1 H), 4.78 (t, J = 347.1499 one 8.8 Hz, 1 H), 4.28 (dd, J = 45,15 Hz, 2 H), (M+HY 4.21 dd, J = 8.5, 3.5 Hz, 1 H 57: (S)—3-(2- 8.13 (d, J = 5.8 Hz, 1 H), 7.37 (d, J = 5.8 HRMS(B) (benzylamino)pyrimidin Hz, 1 H), 7.28 (d, J = 4.5 Hz, 4 H), 7.20 m/z y|)isopropy|oxazo|idin- (dq, J = 8.5, 4.2 Hz, 1 H), 4.54 (br s, 1 H), 312.1584 2-one 4.55 (dd, J = 51,15 Hz, 2 H), 4.35 — 4.29 M+ (m, 2 H), 2.31 (br s, 1 H), 0.77 (br s, 3 H), 0.72 br d, J = 5.5 Hz, 3 H 58: (4S)—4-isopropy|—3-(2- 8.23 (d, J = 5.8 Hz, 1 H), 7.40 (d, J = 5.8 HRMS(B) (1 -(4-(4-methy|piperazin- Hz, 1 H), 7.28 — 7.24 (m, 2 H), 7.01 — 5.98 m/z 1- (m, 2 H), 4.85 — 4.82 (m, 1 H), 4.44 — 4.39 51 y|)phenyl)ethylamino)pyri (m, 2 H), 4.03 — 3.98 (m, 1 H), 3.93 — 3.90 (M+HY midinyl)oxazolidin (m, 4 H), 3.30 (s, 3 H), 3.21 — 3.18 (m, 4 one H), 2.50 (dtt, J = 10, 5.9, 3.5 Hz, 1 H), 1.37 (d, J = 7.1 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 3 H,0.87 d,J=5.9 Hz,3H 59: (S)—3-(2-((S)—1-(3,5- 8.17 (br d, J = 5.0 Hz, 1 H), 7.93 (s, 2 H), HRMS(B) bis(trifluoromethy|)phenyl) 7.82 (s, 1 H), 7.40 (d, J = 5.9 Hz, 1 H), m/z eth lamino p rimidin |- 5.21 q,J =7.1Hz,1H,4.59 brs, 1 H 463.1564 4.33 — 4.25 (m, 2 H), 1.69 (br s, 1 H), 1.57 one d,J=7.1Hz,3H,0.57 brs,6H 60: (S)—4-isopropy|—3-(2- 8.14 (d, J = 5.8 Hz, 1 H), 7.71 (d, J = 8.6 ) ((S)(6- Hz, 1 H), 7.67 — 7.64 (m, 2 H), 7.42 (dd, J m/z methoxynaphthalen = 8.3, 1.8 Hz, 1 H), 7.33 (d, J = 5.8 Hz, 1 84 y|)ethy|amino)pyrimidin H), 7.19 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J = (M + H)+ y|)oxazolidinone 9.1, 2.5 Hz, 1 H), 5.15 (q, J = 7.1 Hz, 1 H), 4.59 (br s, 1 H), 4.29 (t, J = 8.8 Hz, 1 H), 4.24 — 4.19 (br m, 1 H), 3.88 (s, 3 H), 1.74 (br s, 1 H), 1.58 (d, J = 7.1 Hz, 3 H), 0.39 61: (S)—4-isopropyI(2- 8.09 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.9 HRMS(B) ((R)(3- Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 6.92 — m/z methoxyphenyl)ethylamin 6.90 (m, 2 H), 6.75 (ddd, J = 8.1, 2.5, 1.0 357.1927 o)pyrimidin Hz, 1 H), 4.94 — 4.89 (m, 1 H), 4.46 (br s, 1 (M + H)+ y|)oxazolidinone H), 4.34 — 4.23 (m, 2 H), 3.75 (s, 3 H), 2.65 (dtd, J = 14, 6.9, 3.5 Hz, 1 H), 1.49 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 d,J=6.9Hz,3H 62: (S)—3-(2-((S)—1-(3- 8.14 (d, J 5.8 Hz, 1 H), 7.48 (s, 1 H), 7.37 HRMS(B) bromophenyl)ethylamino) — 7.28 (m, 3 H), 7.20 (t, J = 7.1 Hz, 1 H), m/z pyrimidinyl)—4- 5.01 (q, J = 7.1 Hz, 1 H), 4.62 (br s, 1 H), 405.0937 isopropyloxazolidinone 4.34 — 4.26 (m, 2 H), 1.83 (br s, 1 H), 1.50 (M + H)+ (d, J = 7.1 Hz, 3 H), 0.71 (br s, 3 H), 0.59 63: (S)—3-(2-((S)—1-(4- 8.13 (d, J 5.8 Hz, 1 H), 7.44 — 7.41 (m, 2 HRMS(B) bromophenyl)ethylamino) H), 7.35 (d, J = 5.8 Hz, 1 H), 7.26 — 7.22 m/z pyrimidiny|) (m, 2 H), 4.98 (q, J = 7.1 Hz, 1 H), 4.60 (br 405.0912 isopropyloxazolidinone s, 1 H), 4.33 — 4.26 (m, 2 H), 1.73 (br s, 1 (M + H)+ H), 1.49 (d, J = 7.1 Hz, 3 H), 0.68 (br s, 3 , 0.58 brs, 3 H 64: (S)—3-(2-(1- 8.23 (d, J = 8.1 Hz, 1 H), 8.07 (d, J = 5.8 ) (naphthalen Hz, 1 H), 7.88 — 7.86 (m, 1 H), 7.73 (d, J = m/z y|)ethy|amino)pyrimidin 8.1 Hz, 1 H), 7.58 (d, J = 7.1 Hz, 1 H), 7. 4 335.1500 y|)oxazolidinone — 7.45 (m, 2 H), 7.42 — 7.39 (m, 1 H), 7.29 (M + H)+ (d, J = 5.8 Hz, 1 H), 5.90 (q, J = 6.7 Hz, 1 H), 4.32 (br s, 1 H), 4.22 (br s, 1 H), 3.98 (br s, 1 H), 3.37 (br s, 1 H), 1.65 (d, J = 6.9 65: (S)—3-(2-((S)—1- 8.11 (d, J = 5.8 Hz, 1 H), 7.80 — 7.77 (m, 1 HRMS(B) (naphthalen H), 7.73 — 7.68 (m, 2 H), 7.56 (s, 1 H), 7.45 m/z y|)ethy|amino)pyrimidin — 7.40 (m, 2 H), 7.37 (d, J = 5.8 Hz, 1 H), 411.1820 y|)pheny|oxazo|idin 7.23 (dd, J = 8.6, 1.5 Hz, 1 H), 7.08 — 7.00 (M + H)+ one (m, 5 H), 5.80 (dd, J = 8.8, 3.8 Hz, 1 H), .07 (q, J = 6.9 Hz, 1 H), 4.79 (t, J = 8.7 Hz, 1 H), 4.20 (dd, J = 8.6, 3.5 Hz, 1 H), 1.55 d, J = 6.9 Hz, 3 H 66: (R)—3-(2-((S)—1- 8.10 (d, J = 5.8 Hz, 1 H), 7.82 — 7.78 (m, 3 HRMS(B) (naphthalen H), 7.69 (s, 1 H), 7.47 — 7.40 (m, 5 H), 7.38 m/z y|)ethy|amino)pyrimidin — 7.29 (m, 4 H), 5.53 (dd, J = 8.8, 3.8 Hz, 1 411.1821 y|)pheny|oxazo|idin H), 4.82 (q, J = 6.9 Hz, 1 H), 4.68 (t, J = (M + H)+ one 8.6 Hz, 1 H), 4.15 (dd, J = 8.6, 4.0 Hz, 1 , 1.31 d,J =6.9 Hz, 3 H 67: (S)—3-(2-((R)—1-(3- 8.10 (d, J 5.8 Hz, 1 H), 7.53 — 7.50 (m, 1 ) bromophen Ieth lamino H — 7.31 , 7.36 m, 3 H 7.21 , t, J = 7.8 pyrimidinyl)—4- Hz,1FD,494——486(m,1ffi,442(br&1 m/z isopropyloxazolidinone ffi,433(dd.J=94,25,1FD,426(LJ= 405.0930 88Ffi,1H)265(dm,J=14,7OJ&8Hz 1H)1MM¢J=7JHL3H)100wJ= (M+HY 7JHL3H,085dJ=7JHL3H 68: (S)—3-(2-((R)—1-(4- 840kLJ58HL1H)745—742mn2 HRMS(B) heny|)ethy|amino) H)735wflJ=59HL1H)729—725 m/z dinyl)—4- (m,2FD,495——490(WL1ffi,444(br&1 405.0934 isopropyloxazolidinone H)434—425mL2H)263me=14 (M+HY 6935HL1H)149wJ=74HL3H) 098@J=74H;3H)084@J=74 69: (S)—4-isopropyI(2- 8.12 (d, J = 5.8 Hz, 1 H), 7.34 (d, J = 6.0 HRMS(B) «$443 Hz, 1 H), 7.20 — 7.16 (m, 1 H), 6.89 — 6.87 m/z methoxyphenyl)ethylamin (m, 2 H), 6.75 — 6.73 (m, 1 H), 4.99 (q, J = 357.1918 o)pyrimidin 6.7 Hz, 1 H), 4.63 (br s, 1 H), 4.34 — 4.25 (M+HY y|)oxazo|idinone (m, 2 H), 3.74 (s, 3 H), 1.84 (br s, 1 H), 1.49 (d, J = 7.1 Hz, 3 H), 0.68 (br s, 3 H), 0.57 br s, 3 H 70: (S)—4-isopropy|—3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.9 HRMS(B) «$4?- Hz, 1 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.08 (d, m/z tolylethylamino)pyrimidin- J = 8.1 Hz, 2 H), 4.99 (q, J = 7.1 Hz, 1 H), 341.1977 4-y|)oxazo|idinone 4.63 (br s, 1 H), 4.34 — 4.26 (m, 2 H), 2.28 (M+HY (s, 3 H), 1.86 (brs, 1 H), 1.48 (d, J = 7.1 Hz, 3 H , 0.69 brs, 3 H , 0.58 brs, 3 H 71: tert-buty|—3-(2- 8.14 (d, J = 5.7 Hz, 1 H), 7.37 — 7.34 (m, 2 HRMS(B) «$4- H), 7.30 — 7.26 (m, 2 H), 7.19 — 7.15 (m, 2 m/z phenylethylamino)pyrimidi H), 5.00 (q, J = 6.9 Hz, 1 H), 4.76 (br s, 1 341.1979 ny|)oxazo|idinone H), 4.41 — 4.33 (m, 2 H), 1.48 (d, J = 7.1 (M+HY Hz. 3 H , 0.55 brs, 9 H 72: (S)—4-tert-buty|—3-(2- 8.09 (d, J = 5.7 Hz, 1 H), 7.35 — 7.32 (m, 2 HRMS(B) «RH- H), 7.29 — 7.24 (m, 3 H), 7.19 — 7.15 (m, 1 m/z phenylethylamino)pyrimidi H), 5.01 —4.96 (m, 1 H), 4.68 (brs, 1 H), 341.1974 ny|)oxazo|idinone 4.39 (d, H = 9.2 Hz, 1 H), 4.15 (brs, 1 H), (M+HY 1.50 d,J =7.0 Hz.3 H ,0.94 s, 9 H 73: (R)(2-((S)—1-(3- 8.09 (d, J = 5.8 Hz, 1 H), 7.42 — 7.37 (m, 3 HRMS(B) methoxyphenyl)ethylamin H), 7.34 — 7.28 (m, 3 H), 7.21 (t, J = 7.8 m/z o)pyrimidinyl)—4- Hz, 1 H), 6.86 — 6.83 (m, 2 H), 6.78 — 6.76 391.1768 phenyloxazolidinone (m, 1 H), 5.58 (dd, J = 8.6, 4.0 Hz, 1 H), (M+HY 4.74 (t, J = 8.7 Hz, 1 H), 4.66 — 4.61 (m, 1 H), 4.18 (dd, J = 8.6, 4.0 Hz, 1 H), 3.77 (s, , 1.20 d,J :69 Hz, 3 H 74: (S)—3-(2-((S)—1 - 8.55 (d, J = 4.5 Hz, 1 H), 8.10 (d, J = 6.0 HRMS(B) phenylethylamino)pyrimidi Hz, 1 H), 7.64 (d, J = 6.0 Hz, 1 H), 7.43 (br m/z )(pyridin s, 1 H), 7.26 — 7.15 (m, 4 H), 7.06 (br s, 2 362.1624 y|)oxazo|idinone H), 6.92 (br s, 1 H), 5.84 (dd, J = 8.7, 3.2 (M+HY Hz, 1 H), 4.94 (br s, 1 H), 4.88 — 4.78 (m, 2 H), 4.48 (dd, J = 8.7, 3.2 Hz, 1 H), 1.51 (d, J = 6.9 Hz, 3 H 75: (S)—3-(2-((S)—1 - 8.43 (br s, 2 H), 8.16 (br d, J = 5.0 Hz, 1 ) phenylethylamino)pyrimidi H), 7.65 (br s, 1 H), 7.36 — 7.09 (br m, 6 m/z ny|)(pyridin H), 6.90 (brs, 1 H), 5.88 (brs, 1 H), 4.83 23 y|)oxazo|idinone (t, J = 8.8 Hz, 1 H), 4.78 (br s, 1 H), 4.23 (M+HY brs, 1 H , 1.34 d,J=7.0 Hz,3H 76: S isoprop | 2- 8.11 d, J = 5.8 Hz, 1 H s, 1 H , 7.66 , HRMS B ((R)(3- 7.64 — 7.61 (m, 1 H), 7.53 — 7.49 (m, 2 H), m/z uoromethy|)pheny|)eth 7.36 (d, J = 5.9 Hz, 1 H), 5.05 — 4.99 (m, 1 395.1686 ylamino)pyrimidin H), 4.42 (br s, 1 H), 4.33 (dd, J = 9.1, 3.0 (M + H)+ y|)oxazo|idinone Hz, 1 H), 4.24 (t, J = 8.6 Hz, 1 H), 2.68 — 2.60 (m, 1 H), 1.54 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.0 77: (S)—4-isopropy|—3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.60 (d, J = 8.3 HRMS(B) ((R)(4- Hz, 2 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.36 (d, m/z (trifluoromethy|)pheny|)eth J = 5.8 Hz, 1 H), 5.07 — 5.00 (m, 1 H), 4.39 395.1698 ylamino)pyrimidin (br s, 1 H), 4.33 — 4.30 (m, 1 H), 4.27 — (M + H)+ y|)oxazo|idinone 4.23 (m, 1 H), 2.63 (dtd, J = 14, 7.1, 3.5 Hz, 1 H), 1.54 (d, J = 7.0 Hz, 3 H), 0.98 (d, J=7.1Hz,3H,0.84 d,J=7.1Hz,3H 78: (S)—3-(2-((R)—1-(2- 8.10 (d, J = 5.8 Hz, 1 H), 7.40 — 7.34 (m, 2 HRMS(B) pheny|)ethy|amino)p H), 7.24 — 7.18 (m, 1 H), 7.10 — 7.02 (m, 2 m/z yrimidiny|) H), 5.28 (q, J = 7.1 Hz, 1 H), 4.42 (br s, 1 345.1727 pyloxazolidinone H), 4.32 (dd, J = 9.1, 2.5 Hz, 1 H), 4.24 (t, (M + H)+ J = 8.8 Hz, 1 H), 2.64 (dtd, J = 14, 7.0, 3.8 Hz, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.98 (d, J=7.1Hz,3H,0.84 d,J=7.1Hz,3H 79: (S)—4-methyIphenyl- 8.15 (d, J = 5.8 Hz, 1 H), 7.44 — 7.38 (m, 3 HRMS(B) 3-(2-((S) H), 7.36 — 7.21 (m, 6 H), 7.15 — 7.13 (m, 2 m/z ethylamino)pyrimidi H), 5.40 (br s, 1 H), 4.22 — 4.17 (m, 2 H), 375.1809 ny|)oxazo|idinone 4.15 (br s, 1 H), 1.63 (br s, 3 H), 1.15 (d, J (M + H)+ 80: (S)—4-isopropy|—3-(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 HRMS(B) ((S)(4- Hz, 1 H), 7.22 — 7.19 (m, 2 H), 6.92 — 6.89 m/z morpholinophenyl)ethy|am (m, 2 H), 5.00 — 4.95 (m, 1 H), 4.66 (br s, 1 412.2359 ino)pyrimidin H), 4.58 (br s, 1 H), 4.35 — 4.27 (m, 2 H), (M + H)+ y|)oxazo|idinone 3.82 — 3.80 (m, 4 H), 3.09 — 3.07 (m, 4 H), 1.48 (d, J = 7.1 Hz, 3 H), 0.73 (br s, 3 H), 0.60 br s, 3 H 81: (4R)methy|—4- HRMS(B) phenyI(2-((1-(1-pheny|— m/z 1 H-pyrazoI 441.2049 y|)ethy|)amino)pyrimidin (M + H)+ | oxazolidinone 82: (S)—3-(2-((S)—1-(4- 8.16 (d, J = 5.8 Hz, 1 H), 7.36 (d, J = 5.8 HRMS(B) bromo—3,5- Hz, 1 H), 6.64 (s, 2 H), 5.00 — 4.95 (m, 1 m/z dimethoxyphenyl)ethy|ami H), 4.58 (br s, 1 H), 4.33 — 4.23 (m, 2 H), 465.1134 no)pyrimidinyl)—4- 3.79 (s, 6 H), 1.54 (d, J = 7.0 Hz, 3 H), (M + H)+ o onazolidinone 0.55 br s, 6 H 83: (4S)—3-(2-(1-(1H-indo|- 8.11 (d, J = 5.8 Hz, 0.5 H), 8.09 (d, J = 5.8 HRMS(B) -y|)ethy|amino)pyrimidin- Hz, 0.5 H), 7.52 (s, 0.5 H), 7.46 (s, 0.5 H), m/z 4-y|) 7.32 — 7.29 (m, 2 H), 7.19 — 7.18 (m, 1 H), 366.1928 isopropyloxazolidinone 7.10 (ddd, J = 14, 8.6, 1.5 Hz, 1 H), 6.36 (M + H)+ (dt, J = 4.0, 3.0 Hz, 1 H), 5.11 (q, J = 6.9 Hz, 0.5 H), 5.05 (q, J = 6.8 Hz, 0.5 H), 4.64 (br s, 0.5 H), 4.50 (br s, 0.5 H), 4.33 — 4.19 (m, 2 H), 2.74 — 2.64 (m, 0.5 H), 1.86 (br s, 0.5 H), 1.55 (d, J = 7.1 Hz, 3 H), 1.02 (d, J = 7.1 Hz,1.5 H), 0.86 (d, J = 7.1 Hz,1.5 , 0.57 brs,1.5 H ,0.46 brs,1.5 H 84: (S)(2-((S)(5- 8 8.16 — 8.12 m, 2 H , 7.80 d, J = 9.1 Hz, HRMS(B) bromo—6- 1 H), 7.72 (s, 1 H), 7.56 (dd, J = 8.8, 1.8 m/z methoxynaphthalen Hz, 1 H), 7.37 (d, J = 9.1 Hz, 1 H), 7.32 (d, 84 y|)ethy|amino)pyrimidin J = 5.7 Hz, 1 H), 5.18 (q, J = 6.7 Hz, 1 H), (M+HY y|)isopropy|oxazo|idin- 4.60 — 4.54 (m, 1 H), 4.28 (t, J = 8.8 Hz, 1 2-one H), 4.19 (dd, J = 9.1, 3.0 Hz, 1 H), 3.99 (s, 3 H), 1.72 (brs, 1 H), 1.81 (d, J = 7.1 Hz, 3 H), 0.39 (br d, J = 8.8 Hz, 3 H), 0.43 (br d, J = 8.1 Hz, 3 H 85: (S)—3-(2-((R)—1-(4- 8.09 (d, J = 5.9 Hz, 1 H), 7.38 — 7.33 (m, 3 HRMS(B) fluoropheny|)ethy|amino)p H), 7.04 — 8.98 (m, 2 H), 4.98 (q, J = 8.7 m/z yrimidinyl)—4- Hz, 1 H), 4.48 (br s, 1 H), 4.35 — 4.25 (m, 2 345.1725 isopropyloxazolidinone H), 2.64 (dtd, J = 14, 7.1, 3.5 Hz, 1 H), (M+HY 1.50 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 7.1 Hz,3H,0.85 d,J=7.0Hz,3H 86: (S)isopropyI(2- 8.12 (d, J = 5.8 Hz, 1 H), 7.77 (d, J = 8.1 ) «R7142- Hz, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.80 (t, m/z (trifluoromethy|)pheny|)eth J = 7.8 Hz, 1 H), 7.42 — 7.36 (m, 2 H), 5.58 395.1706 ylamino)pyrimidin (q, J = 6.7 Hz, 1 H), 4.70 (dt, J = 7.8, 3.7 (M+HY y|)oxazolidin0ne Hz, 1 H), 4.38 — 4.31 (m, 2 H), 2.58 (dtd, J = 14, 7.0, 3.8 Hz, 1 H), 1.50 (d, J = 8.9 Hz, 3 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.85 (d, J = 87: (R)methy|—3-(2-((S)— HRMS(B) 1-(naphthalen m/z y|)ethy|amino)pyrimidin 425.1967 y|)—4-phenyloxazolidin (M+HY 88: (S)—3-(2-((S)—1-(4- 8.12 (d, J = 5.8 Hz, 1 H), 7.35 — 7.31 (m, 3 ) fluoropheny|)ethy|amino)p H), 7.03 — 6.97 (m, 2 H), 5.03 (q, J = 7.1 m/z yrimidinyl)—4- Hz, 1 H), 4.66 — 4.63 (br m, 1 H), 4.35 — 345.1724 isopropyloxazolidinone 4.27 (m, 2 H), 1.85 (brs, 1 H), 1.49 (d, J = (M+HY 7.0 Hz, 3 H), 0.71 (br s, 3 H), 0.60 (br s, 3 89: (R)—4-methy|—4-pheny|— (CDCI3) 8.12 (d, J = 5.8 Hz, 1 H), 7.43 (d, J HRMS(B) 3-(2-((S)—1 - = 5.8 Hz, 1 H) 7.32 — 7.20 (m, 8 H), 8.99 m/z phenylethylamino)pyrimidi (br s, 2 H), 5.20 (br s, 1 H), 4.33 (br s, 1 375.1822 ny|)oxazo|idinone H), 4.32 — 4. 27 (m, 2 H), 2.20 (s, 3 H), (M+HY 1.41 d, J = 6.8 Hz, 3 H 90: (S)—4-isopropyI(2- 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 HRMS(B) «$442 Hz, 3 H), 7.20 — 7.18 (m, 2 H), 8.95 (d, J = m/z methoxypheny|)ethylamin 8.1 Hz, 1 H), 6.86—6.82 (m, 1 H), 5.28 (q, 357.1924 o)pyrimidin J = 7.1 Hz, 1 H), 4.83 (brs, 1 H), 4.35— (M+HY y|)oxazolidin0ne 4.26 (m, 2 H), 3.87 (s, 3 H), 1.86 (br s, 1 H), 1.48 (d, J = 6.9 Hz, 3 H), 0.69 (br s, 3 H,0.56 brs,3H 91: (S)—3-(2-(1- 8.08 (d, J = 5.8 Hz, 1 H), 7.82 — 7.78 (m, 4 HRMS(B) (naphthalen H), 7.52 (dd, J = 8.6, 1.5 Hz, 1 H), 7.45 — m/z y|)ethy|amino)pyrimidin 7.38 (m, 2 H), 7.29 (d, J = 5.8 Hz, 1 H), 335.1509 y|)oxazolidin0ne 5.23 (q, J = 6.9 Hz, 1 H), 4.46 — 4.33 (m, 2 (M+HY H), 4.21 — 4.15 (m, 1 H), 3.93 — 3.86 (m, 1 , 1.61 d,J :71 Hz, 3 H 92: isopropy|—3-(2- (CDCI3) 15.12 (br s, 1 H), 9.23 (br s, 1 H), HRMS(B) «$443 7.87 — 7.58 (m, 1 H), 7.24 (dd, J = 8, 8 Hz, m/z methox 1 H — 8.72 m, 3 H — 4.86 , 6.92 , 5.04 m, 371.2082 o)—6-methy|pyrimidin 1H)472—451mL1H)442—425mn y|)oxazo|idinone 2H)3m(&3H)256@3Fm190— hydrochloride 176(nL1 H) 164(brs,3FD,073(d,J= 8HL3H,064¢J=8HL3H 93: (S)—4-isopropyI(6- (CDOQ757—7J9mL6H)505—486 HRMS(B) methyl((S)—1- (m, 1 H), 4.63 — 4.09 (m, 3 H), 2.561 / 2.49 m/z phenylethylamino)pyrimidi (2xg3H)191—170mL1H)162/ 341.1982 n | oxazolidinone 1542xd,3H,075—045nL6H M+H+ 94: (S)—3-(2-(((S)—3- (DM&}m98H(¢J=55HL1H)739 ) methylbutan —732mL2H)731—749mL4H)695 m/z y|)amino)pyrimidiny|)—4- -—682(m,1ffi,583-—573(m,1+fi,482 22 phenyloxazolidinone (LJ=85+t,1H)445(msu1H)137— (M+HY 121mL1H)097w,J=70HL3H) 058 brs,3++,047 brsq3l4 95: (S)—5,5-dimethyI(2- (DMSOwM8AOULJ=55HL1H)739 HRMS(B) (((S)—3-methy|butan —732mL2H)731—723mL2H)748 m/z no)pyrimidiny|)—4- (bns,1FD,693——679(nL1 H),543(s,1 355.2123 phenyloxazolidinone H) 162(S,3FD,130—-114(m,110,096 (M+HY (¢J=65HL3H)QMH&3H)O54w, J=50HL3H,043d,J=50HL3H 96: 3-(2-(((3r,5r,7r)— (DMSO«%)&11axs,1H)745(ms,1 HRMS(B) adamantan H)452—436mL2H)409®r&2H) m/z ylmethyl)amino)pyrimidin- 303(brs,2FD,192(brs,3FD,174— 329.1971 4- | idinone M+H+ 97: (S)—4-isopropy|—3-(2- 8.14 (d, J = 5.8 Hz, 1 H), 7.59 (d, J = 8.1 ) «$444 Hz, 2 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.36 (d, m/z (trifluoromethyl)phenyl)eth J = 5.8 Hz, 1 H), 5.08 (q, J = 6.9 Hz, 1 H), 86 ylamino)pyrimidin 4.59 (br s, 1 H), 4.33 — 4.25 (m, 2 H), 1.57 (M+HY y|)oxazo|idinone (br s, 1 H), 1.54 (d, J = 7.1 Hz, 3 H), 0.60 brs, 3 H ,0.53 brs, 3 H 98: 3-((S)(4-((S)—4- 8.14 (d, J = 5.8 Hz, 1 H), 7.69 — 7.65 (m, 2 HRMS(B) isopropyIoxooxazolidin- H), 7.58 — 7.56 (m, 1 H), 7.48 (t, J = 7.7 m/z 3-y|)pyrimidin Hz, 1 H), 7.37 (d, J = 5.8 Hz, 1 H), 5.09 (q, 352.1764 y|amino)ethy|)benzonitrile J = 7.1 Hz, 1 H), 4.64 (brs, 1 H), 4.35 — (M+HY 4.27 (m, 2 H), 1.74 (brs, 1 H), 1.52 (d, J = 7.1 Hz, 3 H), 0.71 (br s, 3 H), 0.60 (br s, 3 99: (S)—3-(2-((S)—1-(3- 8.14 (d, J = 5.8 Hz, 1 H), 7.36 (d, J = 5.8 HRMS(B) ch|oropheny|)ethy|amino)p Hz, 1 H), 7.32 (br s, 1 H), 7.29 — 7.23 (m, 2 m/z inyl)—4- H), 7.20 — 7.17 (m, 1 H), 5.02 (q, J = 6.9 361.1424 pyloxazolidinone Hz, 1 H), 4,63 (br s, 1 H), 4.34 — 4.27 (m, 2 (M+HY H), 1.82 (brs, 1 H), 1.50 (d, J = 7.1 Hz, 3 , 0.70 brs, 3 H , 0.59 brs, 3 H 100: (4R)—5,5-dimethy|—4- 8.07 (d, J = 5.8 Hz, 0.5 H), 8.06 (d, J = 5.8 HRMS(B) phenyI(2-(1-(4- Hz, 0.5 H), 7.41 — 7.37 (m, 2 H), 7.34 — m/z (piperidin 7.26 (m, 2 H), 7.19 — 7.14 (m, 3 H), 6.95 — 472.2715 y|)phenyl)ethylamino)pyri 6.89 (m, 2 H), 6.81 — 6.78 (m, 1 H), 5.46 (M+HY midinyl)oxazolidin (s, 0.5 H), 5.25 (s, 0.5 H), 4.73 — 4.68 (m, one 0.5 H), 4.60 — 4.55 (m, 0.5 H), 3.12 — 3.07 (m, 4 H), 1.73 — 1.68 (m, 4 H), 1.65 (s, 1.5 H), 1.61 — 1.57 (m, 2 H), 1.54 (s, 1.5 H), 1.41 (d, J = 6.9 Hz,1.5 H), 1.14 (d, J = 6.9 Hz,1.5 H , 0.99 d, J =4.7 Hz, 3 H 101: (S)isopropy|—3-(2- 8.15 (d, J = 5.8 Hz, 1 H), 7.74 (d, J = 8.1 HRMS(B) S 2- Hz, 1 H , 7.69 d, J =8.1Hz,1H,7.58 t, m/z (trifluoromethy|)pheny|)eth J = 7.6 Hz, 1 H), 7.42 — 7.35 (m, 2 H), 5.35 395.1682 ylamino)pyrimidin (q, J = 6.6 Hz, 1 H), 4.65 (dt, J = 8.0, 3.8 (M + H)+ y|)oxazo|idinone Hz, 1 H), 4.35 — 4.26 (m, 2 H), 1.76 (br s, 1 H), 1.52 (d, J = 6.6 Hz, 3 H), 0.64 (br d, J = .5 Hz, 3 H ,0.58 br d, J = 6.3 Hz, 3 H 102: 4,4-dimethyI(2-(1- (CDCI3) 8.22 (d, J = 5.8 Hz, 1 H), 7.87 (s, 1 ) (1-phenyI-1H-pyrazol H), 7.69 — 7.65 (m, 3 H), 7.48 — 7.43 (m, 2 m/z y|)ethylamino)pyrimidin H), 7.35 — 7.28 (m, 2 H), 5.34 (br s, 1 H), 379.1890 y|)oxazo|idinone 5.24 — 5.17 (m, 1 H), 4.09 — 4.05 (m, 2 H), (M + H)+ 1.74 (s, 3 H), 1.64 (d, J = 7.1 Hz, 3 H), 1.58 s, 3 H 103: (S)—3-(2- (DMSO-ds) 8.13 (d, J = 5.5 Hz, 1 H), 7.20 HRMS(B) (((3S,5S,7S)—adamantan- (br s., 1 H), 7.17 (d, J = 5.5 Hz, 1 H), 4.69 m/z 1- — 4.63 (m, 1 H), 4.44 — 4.33 (m, 2 H), 3.11 371.2448 ylmethyl)amino)pyrimidin- — 2.85 (m, 2 H), 2.54 (br s, 1 H), 1.92 (br (M + H)+ 4-y|) s., 3 H), 1.70 — 1.53 (m, 6 H), 1.47 (br s., 6 isopropyloxazolidinone H), 0.93 (d, J = 7.0 Hz, 3 H), 0.78 (d, J = 104: (S)—3-(2-(((S)—1- (DMSO-ds) 8.09 (d, J = 5.5 Hz, 1 H), 7.40 HRMS(B) cyclohexylethyl)amino)pyri — 7.32 (m, 2 H), 7.32 — 7.23 (m, 3 H), 6.83 m/z midiny|)-5,5-dimethyI (d, J = 9.0 Hz, 1 H), 5.42 (s, 1 H), 3.36 (br 395.2446 phenyloxazolidinone s, 1 H), 1.72 — 1.23 (m, 9 H), 1.02 — 0.82 (M + H)+ (m, 10 H), 0.62 (s, 1 H), 0.20 — 0.04 (m, 1 105: (S)—3-(2-(((S)—1- (DMSO-ds) 8.13 (d, J = 5.8 Hz, 1 H), 7.19 HRMS(B) cyclohexylethyl)amino)pyri — 7.09 (m, 2 H), 4.68 (br s, 1 H), 4.41 — m/z midinyl)—4- 4.33 (m, 2 H), 3.77 (br s, 1 H), 2.47 (br s, 1 333.2288 isopropyloxazolidinone H), 1.76 — 1.58 (m, 5 H), 1.43 — 1.35 (m, 1 (M + H)+ H), 1.15 — 1.04 (m, 6 H), 0.97 — 0.88 (m, 5 H,0.77 d,J=6.8 Hz,3H' 106: (4S)—4-isopropy|—3-(2- (DMSO-ds) 8.19 (d, J = 5.6 Hz, 1 H), 7.30 HRMS(B) enoxypropan — 7.24 (m, 3 H), 7.18 (br s, 1 H), 6.96 — m/z y|)amino)pyrimidin 6.85 (m, 3 H), 4.70 — 4.52 (m, 1 H), 4.39 — 357.1921 y|)oxazo|idinone 4.19 (m, 3 H), 4.12 — 4.00 (m, 1 H), 3.92 — (M + H)+ 3.78 (m, 1 H), 2.46 (br s, 1 H), 1.29 — 1.21 m,3H , 0.93—0.58 m,6H 107: (S)(2-(((R) (DMSO-ds) 8.09 (d, J = 5.6 Hz, 1 H), 7.38 HRMS(B) cyclohexylethyl)amino)pyri — 7.12 (m, 6 H), 6.71 (br s, 1 H), 5.36 (s, 1 m/z midiny|)-5,5-dimethyI H), 1.77 — 1.56 (m, 9 H), 1.31 — 1.05 (m, 4 395.2440 phen onazolidinone H + , 0.92 s, 6 H M + H , 0.48 br s., 2 H 108: (S)—3-(5-ch|oro—2- (CDCI3) 8.29 (s, 1 H), 7.84 — 7.74 (m, 4 H), ) -(naphthalen 7.49 — 7.43 (m, 3 H), 5.76 (br s, 1 H), 5.17 m/z y|)ethylamino)pyrimidin — 5.10 (m, 1 H), 4.39 — 4.30 (m, 1 H), 4.31 411.1588 y|)isopropy|oxazo|idin- (t, J = 8.1 Hz, 1 H), 4.09 — 4.05 (m, 1 H), (M + H)+ 2-0ne 1.66 (d, J = 7.0 Hz, 3 H), 1.40 — 1.30 (m, 1 H), 0.52 (d, J = 6.1 Hz, 3 H), 0.27 (br s, 3 109: 4-((S)(4-((S) 8.14 (d, J = 5.8 Hz, 1 H), 7.68 — 7.66 (m, 2 ) isopropyIoxooxazolidin- H), 7.52 (d, J = 8.1 Hz, 3 H), 7.36 (d, J = m/z 3-y|)pyrimidin 5.9 Hz, 1 H), 5.08 (q, J = 7.1 Hz, 1 H), 4.61 352.1775 y|amino)ethy|)benzonitrile (br s, 1 H), 4.34 — 4.26 (m, 2 H), 1.60 (br s, (M + H)+ 1 H), 1.52 (d, J = 7.1 Hz, 3 H), 0.65 (br s, 3 , 0.58 brs, 3 H 110: (S)—4,4-dimethy|—3-(2- ) 8.10 (d, J = 5.8 Hz, 1 H), 8.01 (d, J HRMS(B) 1- naphthalen = 8.6 Hz, 1 H — 7.78 , 7.81 m, 1 H , 7.66 m/z y|)ethy|amino)pyrimidin (d, J = 8.1 Hz, 1 H), 7.52 (d, J = 6.6 Hz, 1 3634822 zolidinone H), 7.48 — 7.39 (m, 2 H), 7.36 — 7.32 (m, 1 (M+HY H), 7.19 — 7.18 (m, 1 H), 5.66 (br s, 2 H), 3.78 — 3.69 (m, 2 H), 1.65 (s, 3 H), 1.64 (s, , 1.35 br s, 3 H 1 11: (R)(2-((S)—1-(4- 8.09 (d, J = 5.7 Hz, 1 H), 7.41 — 7.07 (m, HRMS(B) fluoropheny|)ethy|amino)p 10 H), 5.21 (s, 3 H), 4.96 (q, J = 7.1 Hz,1 m/z yrimidinyl)—5,5- H), 1.50 (s, 3 H), 1.24 (d, J = 7.1 Hz, 3 H), 407.188 dimethyI 0.98 (s, 3 H) (M+HY phenyloxazolidin0ne 112: 4-(1-(4-((S) 8.13 (d, J = 5.8 Hz, 0.5 H), 8.11 (d, J = 5.8 HRMS(B) isopropyIoxooxazolidin- Hz, 0.5 H), 7.85 — 7.80 (m, 2 H), 7.51 (d, J m/z 3-y|)pyrimidin = 8.6 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 406.1553 y|amino)ethy|)benzenesuIf 7.36 (d, J = 5.7 Hz, 0.5 H), 7.35 (d, J = 5.7 (M+HY onamide Hz, 0.5 H), 5.09 (q, J = 6.9 Hz, 0.5 H), 5.03 — 4.97 (br m, 0.5 H), 4.61 (br s, 0.5 H), 4.33 — 4.24 (m, 2.5 H), 2.66 — 2.58 (m, 0.5 H), 1.62 (br s, 0.5 H), 1.532 (d, J = 7.1 Hz, 1.5 H), 1.527 (d, J = 7.1 Hz,1.5 H), 0.98 (d, J = 7.0 Hz, 1.5 H), 0.84 (d, J = 7.0 Hz, 1.5 H , 0.67 brs,1.5 H , 0.56 brs,1.5 H 1 13: (2-((S)(4- 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 ) hydroxyphenyl)ethy|amino Hz, 1 H), 7.12 (d, J 8.1 Hz, 2 H), 6.72 — m/z )pyrimidiny|) 6.68 (m, 2 H), 4.95 (q, J = 6.9 Hz, 1 H), 343.1776 isopropyloxazolidinone 4.69 — 4.65 (m, 1 H), 4.35 — 4.28 (m, 2 H), (M+HY 1.47 (d, J = 7.1 Hz, 3 H), 0.75 (br s, 3 H), 0.62 br s, 3 H 114: (S)(2-(1- (CDCI3) 8.14 (d, J = 5.8 Hz, 1 H), 7.24 (d, J HRMS(B) cyclohexylethylamino)pyri = 5.8 Hz, 1 H), 5.08 (br s, 1 H), 4.10 (s, 2 m/z midiny|)-4,4- H), 3.87 (q, J = 7.0 Hz, 1 H), 1.83 — 1.68 319.2132 dimethyloxazolidin0ne (m, 6 H), 1.75 (s, 3 H), 1.74 (s, 3 H), 1.48 (M+HY (dddd, J = 12, 8.7, 5.7, 2.8 Hz, 1 H), 1.28 — 1.03 m, 4 H 1.17 , d,J :68 Hz, 3 H 1 15: (S)—3-(5-f|uoro—2-((S)— ) 8.15 (d, J = 3.5 Hz, 1 H), 7.83 — HRMS(B) 1-(naphthalen 7.72 (m, 4 H), 7.49 — 7.42 (m, 3 H), 5.06 — m/z y|)ethy|amino)pyrimidin 5.03 (m, 1 H), 4.35 — 4.28 (m, 2 H), 4.10 — 395.1884 y|)isopropy|oxazo|idin- 4.08 (m, 1 H), 1.65 (d, J = 7.0 Hz, 3 H), (M+HY 2-one 1.33 — 1.26 (m, 1 H), 0.38 (br s, 3 H), 0.14 1 16: (S)—3-(5-ch|oro—2- (DMSO-da) 8.39 — 8.31 (m, 2 H), 7.35 — HRMS(B) «$4- 7.32 (m, 2 H), 7.28 (t, J = 7.8 Hz, 2 H), m/z phenylethylamino)pyrimidi 7.17 (t, J = 7.8 Hz, 1 H), 4.89 -4.82 (m, 1 361.1431 ny|) H), 4.49 — 4.45 (m, 2 H), 4.16 (br s, 1 H), (M+HY isopropyloxazolidinone 1.42 (d, J = 7.0 Hz, 3 H), 1.24 (br s, 1 H), 0.86 — 0.78 m, 3 H , 0.48 br s, 3 H 1 17: (2-((S)(4- 8.16 (d, J = 5.8 Hz, 1 H), 7.36 (d, J = 5.8 HRMS(B) bromo—3,5- Hz, 1 H), 6.64 (s, 2 H), 5.00 — 4.95 (m, 1 m/z dimethoxyphenyl)ethylami H), 4.58 (br s, 1 H), 4.33 — 4.23 (m, 2 H), 465.1134 no)pyrimidinyl)—4- 3.79 (s, 6 H), 1.54 (d, J = 7.0 Hz, 3 H), (M+HY isopropyloxazolidinone 0.55 (br s, 6 H) 118: (4S)—3-(2-(1-(3,4- 8J2wJ=58HL05HL810mJ=58 HRMS(B) dimethox phen leth Iami Hz,0511,735——732 m,1f+,697—— m/z 2012/055133 no)pyrimidinyl)—4- 6.85 (m, 3 H), 5.00 — 4.91 (m, 1 H), 4.65 3872035 pyloxazolidinone (br s, 0.5 H), 4.55 (br s, 0.5 H), 4.36 — 4.27 (M+HY (m, 2 H), 3.80 — 3.79 (m, 6 H), 2.69 — 2.61 (m, 0.5 H), 1.87 (br s, 0.5 H), 1.50 (d, J = 7.1 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 1.5 H), 0.86 (d, J = 7.0 Hz,1.5 H), 0.69 (br s,1.5 , 0.60 brs,1.5 H 1 19: (S)(2-(1-(6- (CDCI3) 8.09 (d, J = 5.8 Hz, 1 H), 7.64 — HRMS(B) methoxynaphthalen 7.59 (m, 3 H), 7.36 (dd, J = 8.3, 1.8 Hz, 1 m/z y|)ethy|amino)pyrimidin H), 7.20 — 7.18 (m, 1 H), 7.07 — 7.03 (m, 2 393.1925 y|)-4,4-dimethyloxazolidin- H), 5.56 (br s, 1 H), 5.07 — 5.03 (br m, 1 (M+HY 2-one H), 3.91 — 3.82 (m, 5 H), 1.61 (s, 3 H), 1.56 d,J=6.8 Hz,3H,0.97 brs,3H 120: (S)—5,5-dimethy|—3-(2- 8.09 (d, J = 5.8 Hz, 1 H), 7.81 — 7.79 (m, 1 HRMS(B) ((S)(naphthalen H), 7.74 — 7.68 (m, 2 H), 7.52 (br s, 1 H), m/z y|)ethy|amino)pyrimidin 7.46 — 7.41 (m, 3 H), 7.18 (br s, 1 H), 7.02 31 y|)pheny|oxazo|idin (br s, 2 H), 6.99 (s, 3 H), 5.43 (s, 1 H), 5.02 (M+HY one (q, 6.6 Hz, 1 H), 1.62 (s, 3 H), 1.53 (d, J = 6.6 Hz, 3 H , 0.93 s, 3 H 121: (S)(2-((S)(4- 8.08 (d, J = 5.8 Hz, 1 H), 7.44 (d, J = 5.8 HRMS(B) bromopheny|)ethy|amino) Hz, 1 H), 7.29 — 7.24 (m, 5 H), 7.06 (br s, 2 m/z pyrimidinyl)—5,5- H), 6.92 (br s, 2 H), 5.44 (s, 1 H), 4.88 — 467.1088 dimethyI 4.84 (m, 1 H), 1.63 (s, 3 H), 1.42 (d, J = (M+HY phen onazolidinone 7.1 Hz, 3 H ,0.95 s, 3 H 122: (S)(2-((S)—1-(3- 8.07 (d, J = 5.8 Hz, 1 H), 7.42 (d, J = 5.8 HRMS(B) methoxyphenyl)ethylamin Hz, 1 H), 7.28 — 7.21 (m, 3 H), 7.11 — 7.08 m/z o)pyrimidinyl)—5,5- (m, 3 H), 6.72 (dd, J = 8.3, 1.8 Hz, 1 H), 419.2067 dimethyI 6.66 (br s, 1 H), 6.62 (br s, 1 H), 5.46 (s, 1 (M+HY oxazolidin0ne H), 4.80 — 4.74 (m, 1 H), 3.73 (s, 3 H), 1.64 (s, 3 H), 1.42 (d, J = 7.1 Hz, 3 H), 0.98 (s, 123: (S)(2-((S)(4- 8J4wJ=66HL1H)757wJ=66 HRMS(B) —3- Hz,1FD,708——899(m,2+fi,688(ddd,J m/z methoxyphenyl)ethylamin =854220HL1H)507mJ=74HL 375.1824 o)pyrimidinyl)—4- 1H)468@LJ=7837HL1H)440— (M+HY isopropyloxazolidinone 432(m,2ffi,386(s,3FD,199(br31 H)157@J=7JHL3H)075wJ= 7AHL3H,066dJ=7AHL3H 124: (S)(2-((S)(4- 810wJ=58HL1HL739wJ=58 HRMS(B) bromopheny|)ethy|amino) HL1H)729—726mL2H)725—721 m/z pyrimidinyl)—4- 0m3H)7J2de=6328HL2H) 439.0763 phenyloxazolidin0ne 696wJ=86HL2HL580de=86 (M+HY |dz,1FD,487(qHJ=7J Hz,1FD,4J9 @J=86H;1H)420de=8835 ,143dJ=7AHL3H 125: (4S)—4-isopropy|—3-(2- 82%(dJ=64H;05H)82Q(dJ= HRMS(B) W43 H)752@J=74H;2H) m/z morpholinophenyl)ethy|)a 7.46 (dd, J = 5.8, 3.8 Hz, 1 H), 7.43 — 7.34 412.2342 mino)pyrimidin Um3H)586®dJ=8240HL1H) (M+HY y|)oxazolidinone 5mL1Hy442—433mL2H) 262(dm,J=14,70,38Ffi,05+fi,228 (m305rm102w0=74H;15H) 0m(dJ=7JHz15H)088wJ= 741HL15H,073dJ=74H;15H 126: R 2- S 6- 8.10 d,J =5.6 HZ, 1 H ,7.69 d,J =9.1 HRMS B methoxynaphthalen Hz, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.62 (s, m/z y|amino)pyrimidin 1 H), 7.44 — 7.29 (m, 7 H), 7.20 (d, J = 2.5 441 .1929 y|)pheny|oxazo|idin Hz, 1 H), 7.11 (dd, J = 9.1, 2.5 Hz, 1 H), (M+HY one 5.55 (dd, J = 8.8, 3.8 Hz, 1 H), 4.80 (q, J = 7.1 Hz, 1 H), 4.69 (t, J = 8.6 Hz, 1 H), 4.16 (dd, J = 8.6, 4.0 Hz, 1 H), 3.90 (s, 3 H), 1.28 d, J =7.1 Hz, 3 H 127: (S)—4,4-dimethy|—3-(2- ) 8.20 (d, J = 5.8 Hz, 1 H), 7.84 — HRMS(B) (1-(naphthalen 7.79 (m, 4 H), 7.51 — 7.43 (m, 3 H), 7.29 m/z y|amino)pyrimidin (d, J = 5.8 Hz, 1 H), 5.65 (br s, 1 H), 5.19 — 363.1819 y|)oxazolidinone 5.16 (br m, 1 H), 3.98 (d, J = 8.1 Hz, 1 H), (M+HY 3.91 (d, J = 8.1 Hz, 1 H), 1.70 (s, 3 H), 1.66 d, J :69 Hz, 3 H , 1.02 brs, 3 H 128: 4,4-dimethyI(2-(1- (CDCI3) 8.17 (d, J = 5.8 Hz, 1 H), 7.26 — HRMS(B) (4-(piperidin 7.22 (m, 3 H), 6.91 (d, J = 8.6 Hz, 2 H), m/z y|)phenyl)ethylamino)pyri 5.39 (br s, 1 H), 5.01 — 4.94 (m, 1 H), 4.04 396.2396 4-y|)oxazo|idin — 3.99 (m, 2 H), 3.14 — 3.12 (m, 4 H), 1.75 (M+HY one — 1.69 (m, 8 H), 1.61 — 1.57 (m, 2 H), 1.55 d,J =7.1Hz,3 H , 1.34—1.29 brm,2H 129: (S)(2-((S)—1-(3- 8.09 (d, J = 5.8 Hz, 1 H), 7.36 (d, J = 5.8 HRMS(B) methoxyphenyl)ethylamin Hz, 1 H), 7.26 — 7.16 (m, 5 H), 7.11 (t, J = m/z o)pyrimidinyl)—4- 7.8 Hz, 3 H), 6.74 — 6.66 (m, 3 H), 5.81 391.1771 phenyloxazolidinone (dd, J = 8.6, 3.5 Hz, 1 H), 4.86 — 4.79 (m, 2 (M+HY H), 4.23 (dd, J = 8.8, 3.8 Hz, 1 H), 3.73 (s, 1.44 , d, J 7.1 Hz, 3 H 130: (4S)—3-(2-(1-(2,3- 8.11 (d, J = 5.8 Hz, 0.5 H), 8.09 (d, J = 5.8 HRMS(B) dihydrobenzo[b][1,4]dioxin Hz, 0.5 H), 7.34 — 7.33 (m, 1 H), 6.81 — m/z y|)ethy|amino)pyrimidin- 6.71 (m, 3 H), 4.93 — 4.88 (m, 1 H), 4.65 385.1854 4-y|) (br s, 0.5 H), 4.52 (br s, 0.5 H), 4.36 — 4.27 (M+HY isopropyloxazolidinone (m, 2 H), 4.20 — 4.17 (m, 4 H), 2.66 (dtd, J = 14, 6.9, 3.5 Hz, 0.5 H), 1.99 (br s, 0.5 H), 1.456 (d, J = 7.1 Hz, 1.5 H), 1.454 (d, J = 7.1 Hz,1.5 H), 1.00 (d, J = 7.1 Hz,1.5 H), 0.85 (d, J = 7.1 Hz,1.5 H), 0.75 (br s,1.5 , 0.63 brs,1.5 H 131: (4S)—4-isopropy|—3-(2- 8.545 (d, J = 6.1 Hz, 0.5 H), 8.540 (d, J = HRMS(B) (1 din 6.1 Hz, 0.5 H), 8.39 (dt, J = 49,16 Hz,1 m/z y|)ethy|amino)pyrimidin H), 8.13 (dd, J = 11, 5.7 Hz, 1 H), 7.86 — 328.1771 y|)oxazolidinone 7.80 (m, 1 H), 7.40 — 7.36 (m, 2 H), 5.12 (M+HY (q, J = 7.1 Hz, 0.5 H), 5.02 (m, 0.5 H), 4.65 (br s, 0.5 H), 4.42 (br s, 0.5 H), 4.35 — 4.25 (m, 2 H), 2.67 — 2.62 (m, 0.5 H), 1.76 (br s, 0.5 H), 1.56 (d, J = 7.1 Hz, 1.5 H), 1.55 (d, J = 7.1Hz,1.5 H), 0.99 (d, J = 7.1Hz,1.5 H), 0.85 (d, J = 7.1 Hz,1.5 H), 0.70 (br s, 1.5 H , 0.60 brs,1.5 H 132: (S)—4-benzyI(2- 8.17 (d, J = 5.5 Hz, 1 H), 7.46 (d, J = 6.0 HRMS(B) (cyclopropylamino)pyrimid Hz, 1 H), 7.32 — 7.18 (m, 4 H), 7.15 (d, J = m/z iny|)oxazo|idinone 7.0 Hz, 2 H), 5.04 — 4.91 (m, 1 H) 5.39 (br 311.1515 s, 1 H), 4.25 — 4.11 (m, 2 H), 3.51 (d, J: (M+HY 13.0 Hz, 1 H), 2.80 (dd, J = 13.3, 9.79 Hz, 1 H), 2.76 — 2.69 (m, 1 H), 0.84 — 0.71 (m, 2H ,0.60—0.47 m,2H 133: (S)—4-benzyI(2- (CDCI3) 8.18 (d, J = 5.5 Hz, 1 H), 7.48 (d, J c clohex lamino p rimidi = 6.0 Hz, 1 H 7.42 — 7.31 , m, 3 H , 7.26 ny|)oxazo|idinone w,J=70HL2H)556wr&1H)502 m/z ,3635+t,1H)433—422 353.1979 96—383mL1HL353w,J= 12.6 Hz, 1 H), 2.85 (dd, J = 13.3, 9.8 Hz, 1 (M+HY H)189—1J5mL2H)2J6—205mn2 H) 173—-163(nL1 H) 152——126(m,7 134: benzyI(2- 8.17 (d, J = 5.8 Hz, 1 H), 7.38 (d, J = 5.8 HRMS(B) (benzylamino)pyrimidin Hz, 1 H), 7.36 — 7.30 (m, 2 H), 7.30 — 7.11 m/z y|)oxazo|idinone (m, 6 H), 7.02 (br s, 2 H), 4.95 (br s, 1 H), 361.1669 4.76 — 4.65 (m, 1 H), 4.65 — 4.55 (m, 1 H), (M+HY 4.30 (t, J = 8.4 Hz, 1 H), 4.26 — 4.18 (m, 1 H 1 H 1 H , 3.05 brs, , 2.84 brs, 135: (S)—4-benzyI(2- (CDCI3) 8.22 (d, J = 5.5 Hz, 1 H), 7.48 (d, J HRMS(B) «@4- = 5.5 Hz, 1 H), 7.42 — 7.29 (m, 8 H), 7.19 m/z phenylethyl)amino)pyrimid (d, J = 7.0 Hz, 2 H), 5.62 (br s, 1 H), 5.15 375.1817 iny|)oxazo|idinone (t, J = 6.8 Hz, 1 H), 4.77 (br s, 1 H), 4.25 — (M+HY 4.16 (m, 2 H), 3.45 (dd, J = 13.8, 3.3 Hz,1 H), 2.94 (dd, J = 13.6, 9.0 Hz, 1 H), 1.61 d,J=7.0 Hz,3H 136: (4S)—3-(2-(1-(1,3- 8.14 (d, J = 5.8 Hz, 0.5 H), 8.13 (d, J = 5.8 HRMS(B) dimethyI-1H-pyrazol Hz, 0.5 H), 7.42 (s, 0.5 H), 7.35 (s, 0.5 H), m/z y|)ethylamino)pyrimidin 7.35 (d, J = 5.7 Hz, 0.5 H), 7.34 (d, J = 5.8 345.2038 y|)isopropy|oxazo|idin- Hz, 0.5 H), 5.10 — 5.00 (m, 1 H), 4.75 (dq, (M+HY 2-one J = 7.8, 4.0 Hz, 1 H), 4.41 — 4.32 (m, 2 H), 3.76 (s, 1.5 H), 3.74 (s, 1.5 H), 2.64 — 2.57 (m, 0.5 H), 2.41 — 2.32 (m, 0.5 H), 2.18 (s, 3 H), 1.493 (d, J = 7.1 Hz, 1.5 H), 1.488 (d, J = 7.1Hz,1.5 H), 0.97 (d, J = 7.1Hz,1.5 H), 0.88 (d, J = 7.1 Hz, 3 H), 0.78 (d, J = 7.1 Hz, 1.5 H 137: (S)[2-((S)—1,3- (DMSO-ds) 8.10 (m, 1 H), 7.34 (m, 2 H), HRMS(B) dimethyl-butylamino)— 7.26 (m, 3 H), 7.17 (br s, 1 H), 6.83 (s, 1 pyrimidinyl]—5,5- H), 5.39 (s, 1 H), 1.61 (s, 3 H), 1.39 (s, 1 dimethyIphenyl- H), 1.26 (s, 1 H), 1.02 (m, 4 H), 0.90 (s, 3 369.2297 oxazolidinone H), 0.81 (s, 1 H), 0.71 (s, 3 H), 0.41 (s, 3 (M+HY 138: (S)—3-[2-((S)—2- (DMSO-ds) 8.14 (d, J = 5.8 Hz, 1 H), 7.17 HRMS(B) hydroxymethyl- (d, J = 5.8 Hz, 1 H), 7.03 (br s, 1 H), 4.67 m/z ethylamino)—pyrimidin (br s, 1 H), 4.42 — 4.34 (m, 2 H), 3.96 (br s, 307.2141 -dimethyIphenyl- 1 H), 2.46 (m, 1 H), 1.63 (m, 1 H), 1.47 (m, (M+HY oxazolidinone 1 H), 1.21 (m, 1 H), 1.09 (d, J: 6.3 Hz, 3 H), 0.89 (d, J = 7.3 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H), 0.77 d,J=6.8 Hz,3H 139: (S)-4,4-dimethy|—3-(2- (CDCI3) 8.08 (d, J = 5.8 Hz, 1 H), 7.27 — HRMS(B) (1 7.20 (m, 4 H), 7.17 (d, J = 5.6 Hz, 1 H), m/z ethylamino)pyrimidi 7.15—7.11 (m, 1 H), 5.42 (brs, 1 H), 4.94 313.1668 ny|)oxazo|idinone — 4.87 (m, 1 H), 3.92 — 3.86 (m, 2 H), 1.58 (M+HY (s, 3 H), 1.47 (d, J = 6.9 Hz, 3 H), 1.06 (br s, 3 H 140: (S)(2-((S)—1-(4- (CDCI3) 8.17 (d, J = 5.8 Hz, 1 H), 7.45 — HRMS(B) fluorOohen leth lamino o 7.31 m, 4 H — 7.24 — , 7.28 m, 2 H , 7.09 m/z WO 46136 inyl)—4-methy|—4- 7.06 (m, 2 H), 7.01 — 6.95 (m, 2 H), 5.21 393.1729 phenyloxazolidinone (br s, 1 H), 4.20 (s, 2 H), 4.13 (br s, 1 H), (M + H)+ 1.65 brs, 3 H , 1.13 d, J :68 Hz, 3 H 141: (4S)—4-methy|—4- (CDCI3) 8.14 (d, J = 5.8 Hz, 0.35 H), 8.12 ) phenyI(2-(1-(4- (d, J = 5.8 Hz, 0.65 H), 7.42 — 7.27 (m, 6 m/z (piperidin H), 7.04 (d, J = 8.6 Hz, 0.65 H), 6.91 — 458.2551 y|)phenyl)ethylamino)pyri 6.82 (m, 3.35 H), 5.16 (br s, 0.35 H), 5.02 (M + H)+ midiny|)oxazo|idin (br s, 0.65 H), 4.30 (s, 1.3 H), 4.22 (s, 0.7 one H), 4.19 (br s, 1 H), 3.16 — 3.13 (m, 4 H), 2.20 (s, 1.95 H), 1.79 — 1.70 (br m, 5.05 H), 1.62 — 1.56 (m, 2 H), 1.37 (d, J = 6.8 Hz,1.95 H , 1.06 d, J = 6.3 Hz, 1.05 H 142: (S)benzy|—3-(2- 8.15 (d, J = 5.77 Hz, 1 H), 7.40 — 7.30 (m, HRMS(B) (((S)—1- 3 H), 7.25 — 7.13 (m, 5 H), 7.07 (t, J = 7.0 m/z phenylethyl)amino)pyrimid Hz, 1 H), 6.91 (br s, 2 H), 5.13 (q, J = 7.0 375.1817 iny|)oxazo|idinone Hz, 1 H), 5.01 (t, J = 7.4 Hz, 1 H), 4.34 (t, J (M + H)+ = 8.5 Hz, 1 H), 4.20 (dd, J = 8.9, 2.4 Hz, 1 H), 2.64 (br s, 1 H), 2.47 (br s, 1 H), 1.54 d,J=7.3 Hz,3H 143: (R)benzy|—3-(2- (CDCI3) 8.19 (d, J = 5.0 Hz, 1 H), 7.62 (d, J HRMS(B) (cyclopropylamino)pyrimid = 6.0 Hz, 1 H), 7.41 — 7.29 (m, 4 H), 7.26 — m/z iny|)oxazo|idinone 7.19 (m, 2 H), 6.42 (br s, 1 H), 5.07 (t, J = 311.1516 8.3 Hz, 1 H), 4.30 — 4.24 (m, 2 H), 3.60 (d, (M + H)+ J = 12.6 Hz, 1 H), 2.97 — 2.79 (m, 2 H), 0.95 — 0.81 m, 2 H — 0.62 , 0.75 m, 2 H 144: (R)benzy|—3-(2- 8.12 (d, J = 6.0 Hz, 1 H), 7.36 — 7.28 (m, 3 HRMS(B) (cycloheptylamino)pyrimidi H), 7.28 — 7.19 (m, 3 H), 5.15 — 5.05 (m, 1 m/z ny|)oxazo|idinone H), 4.37 (t, J = 8.5 Hz, 1 H), 4.30 — 4.24 367.2134 (m, 1 H), 4.04 (br s., 1 H), 3.09 (dd, J = (M + H)+ 13.6, 8.0 Hz, 1 H), 2.11 — 1.94 (m, 2 H), 1.78—1.48 m, 11 H 145: (R)benzy|—3-(2- (CDCI3) 8.18 (d, J = 5.0 Hz, 1 H), 7.48 (d, J HRMS(B) hexylamino)pyrimidi = 6.0 Hz, 1 H), 7.42 — 7.29 (m, 3 H), 7.26 m/z ny|)oxazo|idinone (d, J = 7.0 Hz, 2 H), 5.55 (br s, 1 H), 5.10 — 353.1981 4.94 (m, 1 H), 4.33 — 4.22 (m, 2 H), 3.96 — (M + H)+ 3.82 (m, 1 H), 3.53 (d, J = 12.1 Hz, 1 H), 2.85 (dd, J = 13.3, 9.8 Hz, 1 H), 2.22 — 2.01 (m, 2 H), 1.81 (td, J = 13.6, 4.0 Hz, 2 H), 1.68 (dd, J = 9.0, 3.5 Hz, 1 H), 1.51 — 146: (R)benzy|—3-(2- 8.17 (d, J = 5.8 Hz, 1 H), 7.38 (d, J = 6.0 HRMS(B) (benzylamino)pyrimidin Hz, 1 H), 7.35 — 7.30 (m, 2 H), 7.29 — 7.18 m/z y|)oxazo|idinone (m, 5 H), 7.15 (t, J = 7.3 Hz, 1 H), 7.02 (br 59 3, 2 H), 4.95 (br s, 1 H), 4.75 — 4.65 (m, 1 (M + H)+ H), 4.65 — 4.56 (m, 1 H), 4.30 (t, J = 8.5 Hz, 1 H), 4.27 — 4.20 (m, 1 H), 3.05 (br s, 1 H 1 H , 2.82 brs, 147: (R)benzy|—3-(2- (CDCI3) 8.21 (d, J = 5.5 Hz, 1 H), 7.50 (d, J HRMS(B) (((R) = 6.0 Hz, 1 H), 7.43 — 7.29 (m, 5 H), 7.28 — m/z phenylethyl)amino)pyrimid 7.12 (m, 4 H), 7.00 (br s., 2 H), 5.97 (br 3, 375.1822 iny|)oxazo|idinone 1 H), 5.17 (t, J = 6.8 Hz, 1 H), 5.03 — 4.89 (M + H)+ (m, 1 H), 4.28 (t, J = 8.5 Hz, 1 H), 4.19 (dd, J = 9.0, 3.0 Hz, 1 H), 2.97 (br s, 1 H), 2.53 , 1.63 d, J=7.0 Hz, 3 H 148: R benz I 2- CDCI3 8.21 d, J = 6.0 Hz, 1 H , 7.49 d, J HRMS B WO 46136 «$4- = 5.5 Hz, 1 H), 7.44 — 7.29 (m, 8 H), 7.19 m/z phenylethyl)amino)pyrimid (d, J = 5.5 Hz, 2 H), 5.59 (br s, 1 H),, 5.15 375.1816 iny|)oxazo|idinone (t, J = 7.0 Hz, 1 H), 4.75 (br s, 1 H), 4.24 — (M+HY 4.15 (m, 2 H), 3.45 (dd, J = 13.8, 3.3 Hz,1 H), 2.94 (dd, J = 13.5, 9.5 Hz, 1 H), 1.51 d,J=7.0 Hz,3 H 149: (S)isopropyI(5- ) 8.13 (s, 1 H), 7.35 — 7.28 (m, 4 H), HRMS(B) methyl((S)—1 - .20 (m, 1 H), 5.73 (brs, 1 H), 5.00 m/z phenylethylamino)pyrimidi — 4.92 (m, 1 H), 4.59 — 4.51 (m, 1 H), 4.38 341.1974 ny|)oxazo|idinone (t, J = 8.8 Hz, 1 H), 4.12 (t, J = 8.8 Hz,1 (M+HY H), 2.14 (s, 3 H), 1.55 (d, J = 5.5 Hz, 3 H), 1.44 (br s, 1 H), 0.59 (d, J = 5.5 Hz, 3 H), 0.53 d, J = 5.0 Hz, 3 H 150: (S)—3-(5-f|uoro((S)— (CDCI3) 8.18 (d, J = 3.0 Hz, 1 H), 7.32 — HRMS(B) 1- 7.28 (m, 4 H), 7.25 — 7.20 (m, 1 H), 5.54 m/z phenylethylamino)pyrimidi (br s, 1 H), 4.92 — 4.87 (m, 1 H), 4.47 — 345.1724 ny|) 4.40 (m, 1 H), 4.39 (t, J = 8.5 Hz, 1 H), (M+HY isopropyloxazolidinone 4.17 (t, J = 8.5 Hz, 1 H), 1.85 (brs, 1 H), 1.54 (d, J = 7.0 Hz, 3 H), 0.58 — 0.55 (m, 5 151: (S)isopropy|—3- (CDCI3) 8.11 (s, 1 H), 7.24 — 7.20 (m, 1 H), HRMS(B) (%«$4%3 5.94 — 5.89 (m, 2H), 5.75 (dd, J = 7.5 Hz, J m/z methoxyphenyl)ethy|a = 2.5 Hz, 1 H), 5.99 (brs, 1 H), 4.97 (quin, 371.2083 mino)—5- J = 5.8 Hz, 1 H), 4.58 (td, J = 8.8 Hz, J = (M+HY methylpyrimidin 5.1 Hz, 1 H), 4.39 (t, J = 8.8 Hz, 1 H), 4.13 y|)oxazo|idinone (t, J = 8.5 Hz, 1 H), 3.80 (s, 3 H), 2.15 (s, 3 H), 1.52 — 1.55 (m, 1 H), 1.57 (d, J = 5.5 Hz, 3 H), 0.54 (d, J = 7.1 Hz, 3 H), 0.59 (d, J = 7.1 Hz, 3 H 152: (S)isopropyI(5- ) 8.13 (s, 1 H), 7.81 — 7.74 (m, 4 H), HRMS(B) methyl((S)—1 - 7.48 — 7.40 (m, 3 H), 5.87 (br s, 1 H), 5.17 (naphthalen — 5.10 (m, 1 H), 4.42 (td, J = 8.7 Hz, J = y|)ethylamino)pyrimidin 4.8 Hz, 1 H), 4.29 (t, J = 8.8 Hz, 1 H), 4.02 391.2135 y|)oxazo|idinone (t, J = 8.5 Hz, 1 H), 2.13 (s, 3 H), 1.54 (d, J 1 (M+HY = 7.0 Hz, 3 H), 1.35 — 1.28 (m, H), 0.42 (d, J = 7.1 Hz, 3 H), 0.17 (d, J = 7.0 Hz, 3 153: (S)—3-(5-f|uoro((S)— (CDCI3) 8.15 (d, J = 2.5 Hz, 1 H), 7.23 (t, J 1-(3- = 7.8 Hz, 1 H), 5.91 — 5.83 (m, 2 H), 5.78 methoxyphenyl)ethylamin —5.74 (m, 1 H), 5.05 (brs, 1 H), 4.85 (brs, o)pyrimidinyl)—4- 1 H), 4.49 — 4.38 (m, 2 H), 4.19 (t, J = 7.8 isopropyloxazolidinone Hz, 1 H), 3.79 (s, 3 H), 1.54 (d, J = 8.0 Hz, 3 H), 1.32 — 1.25 (m, 1 H), 0.55 — 0.58 (m, 154: (S)—4-methy|—3-(2- ) 8.17 (d, J = 5.8 Hz, 1 H), 7.84 — HRMS(B) ((S)—1-(naphthalen 7.78 (m, 3 H), 7.55 (s, 1 H), 7.51 — 7.43 m/z y|)ethylamino)pyrimidin (m, 5 H), 7.39 — 7.35 (m, 1 H), 7.29 — 7.25 425.1972 y|)pheny|oxazo|idin (m, 3 H), 5.54 (brs, 1 H), 4.31 (brs, 1 H), (M+HY one 4.19 — 4.12 (m, 2 H), 1.84 (br s, 3 H), 1.24 d,J=5.8Hz,3H 155: (S)—3-(2-((S)—1-(6- (CDCI3) 8.18 (d, J = 5.8 Hz, 1 H), 7.59 (t, J HRMS(B) ynaphthalen = 7.8 Hz, 2 H), 7.47 — 7.41 (m, 4 H), 7.38 — y|)ethylamino)pyrimidin 7.34 (m, 1 H), 7.28 — 7.23 (m, 3 H), 7.17 — y|)methy|—4- 7.13 (m, 2 H), 5.31 (brs, 1 H), 4.31 (brs,1 455.2081 phen onazolidinone H , 4.19—4.13 m, 2 H , 3.94 s, 3 H —(brs, 3 H), 1.20 (d, J = 6.6 Hz, 3 H) (M + H)+ 156: (S)—3-(2-((S)—1- (CDCI3) 8.11 (d, J = 5.8 Hz, 1 H), 7.38 — HRMS(B) cyclohexylethylamino)pyri 7.32 (m, 5 H), 7.29 — 7.25 (m, 1 H), 4.81 m/z midinyl)methy|—4- (br s, 1 H), 4.31 — 4.26 (m, 2 H), 3.16 (br 3, 381.2280 phenyloxazolidinone 1 H), 2.17 (s, 3 H), 1.77 — 1.57 (m, 6 H), (M + H)+ 1.28 — 1.09 (m, 4 H), 0.99 — 0.85 (m, 2 H), 0.55 br s, 2 H 157: (S)—3-[2-((S)—2- (DMSO-ds) 8.13 (m, 1 H), 7.36 (m, 2 H), HRMS(B) hydroxymethyl- 7.29 (m, 3 H), 7.19 (br s, 1 H), 6.65 (s, 1 m/z ethylamino)—pyrimidin H), 5.44 (s, 1 H), 4.30 (br s, 1 H), 2.95 (br 343.1778 y|]-5,5-dimethyIphenyl- s, 1 H), 2.77 (br s, 3 H), 1.61 (s, 3 H), 1.25 (M + H)+ oxazolidinone , 1.04 m, 3 H , 0.92 s, 3 H 158: (S)—5,5-dimethy|—4- (DMSO-ds) 8.10 (d, J = 5.5 Hz, 1 H), 7.37 HRMS(B) phenyl[2-((S)—1,2,2- — 7.33 (m, 2 H), 7.29 — 7.25 (m, 3 H), 7.20 m/z trimethyl-propylamino)— (br s, 1 H), 6.75 (d, J = 10 Hz, 1 H), 5.42 369.2277 pyrimidinyl]—oxazolidin- (s, 1 H), 3.47 (m, 1 H), 1.62 (s, 3 H), 0.96 (M + H)+ 2-0ne (d, J = 6.8 Hz, 3 H), 0.88 (s, 3 H), 0.46 (s, 159: (R)(2-((S)—1- 8.11 (d, J = 6.1 Hz, 1 H), 8.04 (d, J = 8.6 HRMS(B) (naphthalen Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.74 (d, m/z y|)ethy|amino)pyrimidin J = 8.1 Hz, 1 H), 7.60 — 7.56 (m, 1 H), 7.53 411.1823 y|)pheny|oxazo|idin — 7.49 (m, 1 H), 7.46 — 7.44 (m, 1 H), 7.42 (M + H)+ one — 7.31 (m, 5 H), 7.21 — 7.18 (m, 2 H), 5.52 (q, J = 6.9 Hz, 1 H), 5.44 (dd, J = 8.8, 3.8 Hz, 1 H), 4.63 (t, J = 8.7 Hz, 1 H), 4.10 (dd, J = 8.6, 4.0 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 3 160: isopropy|—3-[2- (DMSO-ds) 8.14 (d, J = 5.5 Hz, 1 H), 7.16 HRMS(B) ((S)-1,2,2-trimethy|— (d, J = 5.5 Hz, 1 H), 7.00 (br. s, 1 H), 4.73 m/z propylamino)—pyrimidin — 4.66 (m, 1 H), 4.41 — 4.34 (m, 2 H), 3.92 30 y|]-oxazo|idinone (br s, 1 H), 2.46 (br s, 1 H), 1.05 (d, J = 6.8 (M + H)+ Hz, 3 H), 0.91 (d, J = 7.3 Hz, 3 H), 0.87 (s, 9H ,0.77 d,J=6.8Hz,3H 161: (S)—3-[2-((S)—1- ds) 8.13 (d, J = 5.5 Hz, 1 H), 7.17 HRMS(B) cyclopropyl-ethylamino)— (d, J = 5.5 Hz, 1 H), 7.09 (br s, 1 H), 4.67 — m/z diny|]isopropy|- 4.63 (m, 1 H), 4.37 (m, 2 H), 3.52 — 3.43 291.1812 oxazolidinone (m, 1 H), 2.46 (br s, 1 H), 1.19 (d, J = 6.8 (M + H)+ Hz, 3 H), 1.01 — 0.93 (m, 1 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.77 (d, J = 6.8 Hz, 3 H), 0.41 (m, 1 H), 0.33 (m, 1 H), 0.22 (br s, 1 H), 0.10 br s, 1 H 162: (S)—4-isopropy|—3-(2- 8.13 (d, J = 5.8 Hz, 1 H), 7.34 — 7.28 (m, 5 HRMS(B) ((S)(4- H), 7.09 — 7.05 (m, 1 H), 6.96 — 6.90 (m, 4 m/z phenoxyphenyl)ethy|amin H), 5.06 (q, J = 7.1 Hz, 1 H), 4.71 — 4.67 419.2081 midin (m, 1 H), 4.37 — 4.28 (m, 2 H), 2.08 (br s, 1 (M + H)+ y|)oxazolidinone H), 1.52 (d, J = 7.1 Hz, 3 H), 0.76 (d, J = Hz, 3 H , 0.67 d, J = 7.1 Hz, 3 H 163: (S)—3-(2-((S)—1-(2,3- 8.12 (d, J = 5.6 Hz, 1 H), 7.32 (d, J = 5.6 HRMS(B) dihydrobenzofuran Hz, 1 H), 7.17 (s, 1 H), 7.04 — 7.02 (m, 1 m/z y|)ethy|amino)pyrimidin H), 6.63 (d, J = 8.1 Hz, 1 H), 4.98 (q, J = 369.1915 y|)isopropy|oxazo|idin- 7.1 Hz, 1 H), 4.69 — 4.65 (m, 1 H), 4.51 — (M + H)+ 2-one 4.47 (m, 2 H), 4.36 — 4.27 (m, 2 H), 3.16 — 3.12 (m, 2 H), 2.09 (br s, 1 H), 1.48 (d, J = 7.0 Hz, 3 H , 0.75 d, J = 7.0 Hz, 3 H , 0.65 WO 46136 d_J=7.1Hz,3H — 164: (S)(2-((S)—1-(4- 8.12 (d, J = 5.8 Hz, 1 H), 7.34 — 7.31 (m, 3 HRMS(B) tert- H), 7.24 — 7.21 (m, 2 H), 5.02 (q, J = 7.1 m/z butylpheny|)ethy|amino)py Hz, 1 H), 4.66 — 4.63 (m, 1 H), 4.35 — 4.25 49 rimidiny|) (m, 2 H), 1.95 (br 8,1 H), 1.50 (d, J = 7.0 (M+HY isopropyloxazolidinone Hz, 3 H), 1.29 (s, 9 H), 0.69 (d, J = 7.0 Hz, 3H ,0.58 d,J=6.9Hz,3H 165: (S)[2-((S)—1 - (DMSO-ds) 8.10 (d, J = 5.5 Hz, 1 H), 7.37 HRMS(B) cyclopropyl-ethylamino)— — 7.33 (m, 2 H), 7.30 — 7.24 (m, 3 H), 7.15 m/z pyrimidinyl]—5,5- (br s, 1 H), 7.00 (br s, 1 H), 5.37 (s, 1 H), 353.1974 dimethyIphenyl- 2.82 (br s, 1 H), 1.61 (s, 3 H), 1.07 (d, J = (M+HY oxazolidinone 6.5 Hz, 3 H), 0.89 (s, 3 H), 0.65 (br s, 1 H), 0.17 (br s, 1 H), 0.00 (br s, 1 H), -0.23 (br , ,-0.65 br s, 1 H 166: (S)—3-(5-f|uoro((S)— (DMSO-ds) 8.36 (br s, 1 H), 7.95 (br s, 1 HRMS(B) 1-(4- H), 7.24 (d, J = 8.5 Hz, 2 H), 6.82 (d, J = m/z methoxypheny|)ethylamin 9.0 Hz, 2 H), 6.05 (br s, 1 H), 4.77 (br s, 1 375.1815 o)pyrimidinyl)—4- H), 4.54 — 4.45 (m, 2 H), 4.24 (br s, 1 H), (M+HY isopropyloxazolidinone 3.70 (s, 3 H), 1.38 (d, J = 7.0 Hz, 3 H), 1.26— 1.22 m, 1 H , 0.66—0.47 m, 6 H 167: 5-dimethy|—4- 8.08 (d, J = 5.8 Hz, 1 H), 7.42 — 7.38 (m, 3 HRMS(B) phenyI(2-((S) H), 7.35 — 7.27 (m, 5 H), 7.22 — 7.17 (m, 3 m/z phenylethylamino)pyrimidi H), 5.18 (s, 1 H), 4.62 — 4.57 (m,1 H), 1.51 389.1975 ny|)oxazo|idinone (s, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 0.98 (s, (M+HY 168: (R)—5,5-dimethy|—3- 8.10 (d, J = 5.8 Hz, 1 H), 7.82 (d, J = 8.1 HRMS(B) (2-((S)—1-(naphtha|en Hz, 3 H), 7.73 (s, 1 H), 7.48 — 7.33 (m, 7 m/z y|amino)pyrimidin H), 7.19 (d, J = 7.1 Hz, 2 H), 5.07 (s, 1 H), 439.2132 y|)pheny|oxazo|idin 4.7,4(q J= 1H),1.32(d,J= 8.9 (M+HY 169: (R)(2-((S)—1-(4- 88.1,0(d J= 5.8Hz, 1 H) 7.41— 7.28 (m, HRMS(B) fluoro—3- 8H), 7.02 6.9,7(m 2H), 8.82(ddd,J= m/z methoxypheny|)ethylamin 8.2, 4.4, 2.0 Hz, 1 H), 5.81 (dd, J = 8.8, 4.0 409.1677 o)pyrimidinyl)—4- Hz, 1 H), 4.77 (t, J = 8.8 Hz, 1 H), 4.85 (q, (M+HY phenyloxazolidin-Z-one J = 7.1 Hz, 1 H), 4.19 (dd, J = 9.1, 4.0 Hz, 1 H), 3.83 (s, 3 H), 1.20 (d, J = 7.9 Hz, 3 Example 170: (4S)—4-isopropyI(2-(2,2,2-trifluoro—1-phenylethylamino)pyrimidin y|)oxazolidin0ne WIELLJZO CF3 \\\“‘\\/O A solution of (S)—3-(2-ch|oropyrimidinyl)isopropyloxazolidin-Z-one (163 mg, 0.674 mmol), 2,2,2-trifluoro—1-phenylethanamine (624 mg, 3.56 mmol, 5.3 equiv) and p- toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110 °C for 2 h and treated with additional p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv), then heated at 110 °C for 1 1/2 h. After cooling, the solid reaction mixture was treated with MeCN, sonicated and filtered. The filtrated was concentrated and purified by silica gel column chromatography (EtOAc/Heptane 0 to %) to give (4S)—4-isopropyl(2-(2,2,2-trifluorophenylethylamino)pyrimidin yl)oxazolidinone (65 mg) in 25% yield. 1H NMR (400 MHz, CD30D) 8 8.215 (d, J = 6.1 Hz, 0.5 H), 8.212 (d, J = 6.1 Hz, 0.5 H), 7.52 (t, J = 7.1 Hz, 2 H), 7.46 (dd, J = 5.8, 3.8 Hz, 1 H), 7.43 — 7.34 (m, 3 H), 5.86 (qd, J = 8.2, 4.0 Hz, 1 H), 4.83 — 4.75 (m, 1 H), 4.42 — 4.33 (m, 2 H), 2.62 (dtd, J = 14, 7.0, 3.8 Hz, 0.5 H), 2.28 (br s, 0.5 H), 1.02 (d, J = 7.1 Hz, 1.5 H), 0.91 (d, J = 7.1 Hz, 1.5 H), 0.88 (d, J = 7.11 Hz, 1.5 H), 0.73 (d, J = 7.1 Hz, 1.5 H); HRMS(B) m/z 381.1545 (M + H)+.
Examples 171 and 172 A on of (2-chloropyrimidinyl)isopropyloxazolidinone (106 mg, 0.439 mmol) and 1-(3-fluoropheny|)ethanamine (196 mg, 1.41 mmol, 3.21 equiv) in DMSO (1 mL) was heated at 110 °C for 1 1/2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)—3-(2-((R)—1-(3-fluorophenyl)ethylamino)pyrimidinyl)isopropyloxazolidinone and (S)—3-(2-((S)—1-(3-fluorophenyl)ethylamino)pyrimidinyl)isopropyloxazolidin one. e 171 first eluted product (28 mg) 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.8 Hz, 1 H), 7.36 — 7.27 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.07 (dt, J = 10, 2.0 Hz, 1 H), 6.92 — 6.88 (m, 1 H), 4.98 — 4.93 (m, 1 H), 4.42 (br s, 1 H), 4.32 (dd, J = 9.1, 2.8 Hz, 1 H), 4.26 (t, J = 8.7 Hz, 1 H), 2.64 (dtd, J = 14, 7.1, 3.5 Hz, 1 H), 1.50 (d, J = 7.0 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 345.1729 (M + H)+. e 172 second eluted product (22 mg) 1H NMR (400 MHz, CD30D) 8 8.13 (d, J = .7 Hz, 1 H), 7.36 (d, J = 5.8 Hz, 1 H), 7.29 (td, J = 8.1, 6.1 Hz, 1 H), 7.13 (d, J = 7.6 Hz, WO 46136 2012/055133 1 H), 7.06 — 7.04 (m, 1 H), 6.94 — 6.87 (m, 1 H), 5.03 (q, J = 7.1 Hz, 1 H), 4.64 (br s, 1 H), 4.34 — 4.26 (m, 2 H), 1.79 (br s, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.70 (br s, 3 H), 0.58 (br s, 3 H); HRMS(B) m/z 345.1727 (M + H)+.
Examples 173 and 174 HNJNL/Nj\[[113 O W A solution of (S)(2-ch|oropyrimidinyl)isopropy|oxazo|idinone (90 mg, 0.37 mmol), iPr2NEt (0.455 mL, 2.61 mmol, 7.0 equiv) and 1-(biphenyIy|)ethanamine hydrochloride (87 mg, 0.37 mmol) in DMSO (1 mL) was heated at 110 °C for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined cs were dried over NaZSO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)—3-(2-((R)—1-(biphenyIyl)ethylamino)pyrimidin- 4-y|)isopropy|oxazo|idinone and (S)—3-(2-((S)—1-(biphenyIyl)ethylamino)pyrimidin- 4-y|)isopropy|oxazo|idinone.
Example 173 first eluted product (17 mg) 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.8 Hz, 1 H), 7.59 — 7.54 (m, 4 H), 7.43 — 7.28 (m, 6 H), 5.01 (q, J = 6.8 Hz, 1 H), 4.49 (br s, 1 H), 4.32 (dd, J = 9.1, 3.0 Hz, 1 H), 4.26 (t, J = 8.6 Hz, 1 H), 2.67 (dtd, J = 14, 7.0, 3.5 Hz, 1 H), 1.55 (d, J = 7.1 Hz, 3 H), 1.01 (d, J = 7.1 Hz, 3 H), 0.86 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 403.2141 (M + H)+.
Example 174 second eluted product (21 mg) 1H NMR (400 MHz, CD30D) 8 8.14 (d, J = .8 Hz, 1 H), 7.58 — 7.52 (m, 4 H), 7.42 — 7.28 (m, 6 H), 5.06 (q, J = 7.1 Hz, 1 H), 4.63 (br s, 1 H), 4.34 — 4.25 (m, 2 H), 1.79 (br s, 1 H), 1.55 (d, J = 7.1 Hz, 3 H), 0.65 (br s, 3 H), 0.53 (br s, 3 H); HRMS(B) m/z 403.2139 (M + H)+.
Examples 175 and 176 HN N/ N/(O (Jot wL/ A solution of (S)(2-ch|oropyrimidiny|)isopropy|oxazo|idinone (96 mg, 0.40 mmol) and 1-(4-ch|oropheny|)ethanamine (204 mg, 1.31 mmol, 3.3 equiv) in DMSO (1 mL) was heated at 110 °C for 3 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over , filtered and concentrated. Silica gel column chromatography /Heptane 10 to 50%) provided (S)(2-((R)—1-(4-ch|oropheny|)ethy|amino)pyrimidiny|)isopropy|oxazo|idinone and (S)—3-(2-((S)—1-(4-ch|oropheny|)ethylamino)pyrimidiny|)isopropy|oxazo|idin one.
Example 175 first eluted product (32 mg) 1H NMR (400 MHZ, CD30D) 8 8.10 (d, J = 5.8 Hz, 1 H), 7.36 — 7.28 (m, 5 H), 4.95 (q, J = 6.7 Hz, 1 H), 4.45 (br s, 1 H), 4.35 — 4.26 (m, 2 H), 2.64 (dtt, J = 11, 7.0, 3.4 Hz, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 361.1430 (M + H)+.
Example 176 second eluted product (40 mg) 1H NMR (400 MHz, CDgOD) 8 8.13 (d, J = .7 Hz, 1 H), 7.36 — 7.26 (m, 5 H), 5.00 (q, J = 7.1 Hz, 1 H), 4,62 (br s, 1 H), 4.34 — 4.26 (m, 2 H), 1.77 (br s, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.68 (br s, 3 H), 0.59 (br s, 3 H); HRMS(B) m/z 31 (M + H)+. es 177 and 178 A solution of (S)(2-ch|oropyrimidiny|)isopropy|oxazo|idinone (93 mg, 0.38 mmol) and 1-(3,4-dich|oropheny|)ethanamine (73.1 mg, 0.385 mmol, 1.0 equiv) in DMSO (1 mL) was heated at 110 °C for 1 1/2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column tography (EtOAc/Heptane 10 to 50%) provided (S)—3-(2-((R)—1-(3,4-dichlorophenyl)ethylamino)pyrimidinyl)isopropyloxazolidin one and (S)—3-(2-((S)—1-(3,4-dichlorophenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone.
Example 177 first eluted product (21 mg) 1H NMR (400 MHz, CD30D) 8 8.12 (d, J = 5.8 Hz, 1 H), 7.50 (d, J = 2.0 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.37 (d, J = 5.8 Hz, 1 H), 7.28 (dd, J = 8.6, 2.0 Hz, 1 H), 4.94 — 4.88 (m, 1 H), 4.43 (br s, 1 H), 4.35 — 4.26 (m, 2 H), 2.68 — 2.60 (m, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 395.1035 (M + H)+.
Example 178 second eluted product (28 mg) 1H NMR (400 MHz, CD30D) 8 8.15 (d, J = .8 Hz, 1 H), 7.47 — 7.42 (m, 2 H), 7.37 (d, J = 5.8 Hz, 1 H), 7.25 (dd, J = 8.1, 2.0 Hz, 1 H), 5.01 — 4.96 (m, 1 H), 4.61 (br s, 1 H), 4.34 — 4.26 (m, 2 H), 1.72 (br s, 1 H), 1.50 (d, J = 7.1 Hz, 3 H), 0.67 (br s, 3 H), 0.60 (br s, 3 H); HRMS(B) m/z 395.1044 (M + H)+.
Examples 179 and 180 A solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (86 mg, 0.36 mmol) and 1-(3-(1H-pyrroly|)phenyl)ethanamine (100 mg, 0.537 mmol, 1.5 equiv) in DMSO (1 mL) was heated at 110 °C for 1 1/2 h. The reaction e was d with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)—3-(2-((R)—1-(3-(1H-pyrroly|)phenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone and (S)—3-(2-((S)—1-(3-(1 H-pyrrol yl)phenyl)ethylamino)pyrimidinyl)isopropyloxazolidinone. e 179 first eluted product (14 mg) 1H NMR (400 MHz, CD30D) 8 8. 11 (d, J = 5.8 Hz, 1 H), 7.45 (t, J = 1.8 Hz, 1 H), 7.39 — 7.29 (m, 3 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.13 (t, J = 2.0 Hz, 2 H), 6.25 (t, J = 2.1 Hz, 2 H), 5.03 — 4.97 (m, 1 H), 4.46 (br s, 1 H), 4.31 — 4.20 (m, 2 H), 2.64 (dtd, J = 14, 7.0, 3.8 Hz, 1 H), 1.56 (d, J = 7.1 Hz, 3 H), 0.95 (d, J = 7.1 Hz, 3 H), 0.84 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 392.2092 (M + H)+.
Example 180 second eluted product (10 mg) 1H NMR (400 MHz, CD30D) 8 8.14 (d, J = .7 Hz, 1 H), 7.42 (br s, 1 H), 7.38 — 7.28 (m, 3 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.12 (t, J = 2.3 Hz, 2 H), 6.25 (t, J = 2.0 Hz, 2 H), 5.09 (q, J = 6.9 Hz, 1 H), 4.64 (br s, 1 H), 4.32 — 4.23 (m, 2 H), 1.84 (br s, 1 H), 1.55 (d, J = 7.1 Hz, 3 H), 0.54 (br s, 6 H); HRMS(B) m/z 392.2090 (M + H)+.
Examples 181 and 182 fit 0 HN N/ NAG of U \\ A solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (44 mg, 0.18 mmol) and 1-(4-(1H-pyrrolyl)phenyl)ethanamine (33.9 mg, 0.182 mmol, 1 equiv) in DMSO (1 mL) was heated at 110 °C for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) ed (2-((R)—1-(4-(1H-pyrroly|)phenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone and (S)—3-(2-((S)—1-(4-(1 H-pyrrol yl)phenyl)ethylamino)pyrimidinyl)isopropyloxazolidinone.
Example 181 first eluted product (18 mg) 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.8 Hz, 1 H), 7.44 — 7.39 (m, 4 H), 7.35 (d, J = 5.9 Hz, 1 H), 7.13 (t, J = 2.2 Hz, 2 H), 6.24 (t, J = 2.0 Hz, 2 H), 5.02 — 4.96 (m, 1 H), 4.49 (br s, 1 H), 4.34 — 4.25 (m, 2 H), 2.66 (dtd, J = 14, 7.0, 3.3 Hz, 1 H), 1.53 (d, J = 7.1 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 3 H), 0.86 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 392.2089 (M + H)+. e 182 second eluted product (9 mg) 1H NMR (400 MHz, CD30D) 8 8.14 (d, J = .8 Hz, 1 H), 7.39 (s, 4 H), 7.35 (d, J = 5.9 Hz, 1 H), 7.12 (t, J = 2.2 Hz, 2 H), 6.25 (t, J = 2.0 Hz, 2 H), 5.05 (q, J = 7.1 Hz, 1 H), 4.64 (br s, 1 H), 4.34 — 4.26 (m, 2 H), 1.87 (br s, 1 H), 1.53 (d, J = 7.1 Hz, 3 H), 0.68 (br s, 3 H), 0.57 (br s, 3 H); HRMS(B) m/z 392.2082 (M + H)+.
Examples 183 and 184 “Ii 0 HNAN/ N/(O MeO:©/L\1 \f\.\\/ A mixture of (4S)—3-(2-((1-(3,4-dimethoxyphenyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone (example 118) was resolved on a column (AS-H 4.6 X 100 mm) using 30% iPrOH in C02 to give (2-((R)—1-(3,4- dimethoxyphenyl)ethylamino)pyrimidinyl)isopropy|oxazolidinone and (S)—3-(2- ((S)(3,4-dimethoxyphenyl)ethylamino)pyrimidinyl)isopropy|oxazolidinone.
Example 183 first eluted product (13 mg) 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 Hz, 1 H), 6.97 (br d, J = 1.5 Hz, 1 H), 6.92 — 6.88 (m, 2 H), 4.96 (q, J = 6.7 Hz, 1 H), 4.61 — 4.55 (m, 1 H), 4.35 — 4.28 (m, 2 H), 3.803 (s, 3 H), 3.800 (s, 3 H), 2.63 (dtd, J = 14, 7.0, 3.5 Hz, 1 H), 1.51 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.86 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 387.2031 (M + H)+.
Example 184 second eluted product (10 mg) 1H NMR (400 MHz, CD30D) 8 8.13 (d, J = 5.8 Hz, 1 H), 7.32 (d, J = 5.7 Hz, 1 H), 6.94 (br d, J =1.1 Hz, 1 H), 6.89 — 6.84 (m, 2 H), 4.99 (q, J = 7.1 Hz, 1 H), 4.67 — 4.63 (m, 1 H), 4.36 — 4.26 (m, 2 H), 3.79 (s, 6 H), 2.01 (br s, 1 H), 1.51(d, J = 7.1 Hz, 3 H), 0.71 (d, J = 7.1 Hz, 3 H), 0.63 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 387.2029 (M + H)+. es 185 and 186 A solution of (S)(2-chloropyrimidinyl)isopropy|oxazolidinone (93 mg, 0.38 mmol) and 1-(4-(piperidinyl)phenyl)ethanamine (410 mg, 2.01 mmol, 5.2 equiv) in DMSO (1 mL) was heated at 110 °C for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the s phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 100%) provided (4S)isopropyl(2-((1-(4-(piperidiny|)phenyl)ethyl)amino)pyrimidin y|)oxazo|idinone (57 mg) in 36% yield. A mixture of (4S)—4-isopropyl(2-(1-(4- (piperidinyl)phenyl)ethylamino)pyrimidinyl)oxazolidinone was resolved on a column (AD-H 4.6 x 100 mm) using 5 to 55% MeOH with 0.2% Et2NH in C02 to give (8)- 4-isopropyl(2-((R)—1-(4-(piperidinyl)phenyl)ethylamino)pyrimidinyl)oxazolidin one and (S)—4-isopropyl(2-((S)—1-(4-(piperidinyl)phenyl)ethylamino)pyrimidin zo|idinone.
Example 185 first eluted product (16 mg) 1H NMR (400 MHZ, CD30D) 8 8.10 (d, J = 5.8 Hz, 1 H), 7.31 (d, J = 5.8 Hz, 1 H), 7.24 — 7.20 (m, 2 H), 6.94 — 6.91 (m, 2 H), 4.93 (q, J = 7.1 Hz, 1 H), 4.58 — 4.54 (m, 1 H), 4.34 — 4.27 (m, 2 H), 3.11 — 3.08 (m, 4 H), 2.63 (dtd, J = 14, 7.1, 3.5 Hz, 1 H), 1.73 — 1.67 (m, 4 H), 1.60 — 1.54 (m, 2 H), 1.49 (d, J = 7.1 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.86 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 410.2555 (M + H)+.
Example 186 second eluted t (16 mg) 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.8 Hz, 1 H), 7.31 (d, J = 5.8 Hz, 1 H), 7.20 — 7.16 (m, 2 H), 6.93 — 6.89 (m, 2 H), 4.98 (q, J = 6.9 Hz, 1 H), 4.69 — 4.65 (m, 1 H), 4.36 — 4.26 (m, 2 H), 3.10 — 3.07 (m, 4 H), 2.07 (br s, 1 H), 1.73 — 1.67 (m, J = 4 H), 1.60 — 1.54 (m, 2 H), 1.48 (d, J = 7.1 Hz, 3 H), 0.75 (d, J = 7.0 Hz, 3 H), 0.63 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 410.2556 (M + H)+.
Examples 187 and 188 ”:M0U A solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (96 mg, 0.40 mmol) and 1-(1-phenyl-1H-pyrazolyl)ethanamine (387 mg, 2.97 mmol, 5.2 equiv) in DMSO (1.5 mL) was heated at 110 °C for 1 1/2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the s phase was extracted with EtOAc (3 x 8 mL). Combined cs were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 80%) provided (S)—4-isopropyl(2-((R)—1-(1-phenyl-1H-pyrazolyl)ethylamino)pyrimidin y|)oxazo|idinone and (S)isopropyl(2-((S)—1-(1-phenyl-1H-pyrazol y|)ethylamino)pyrimidinyl)oxazolidinone.
WO 46136 Example 187 first eluted t (13 mg) 1H NMR (400 MHZ, CD30D) 8 8.16 (d, J = 5.8 Hz, 1 H), 8.10 (s, 1 H), 7.70 — 7.66 (m, 3 H), 7.48 — 7.43 (m, 2 H), 7.37 (d, J = 5.7 Hz, 1 H), 7.32 — 7.28 (m, 1 H), 5.20 (q, J = 6.6 Hz, 1 H), 4.75 (dt, J = 7.7, 4.0 Hz, 1 H), 4.40 — 4.33 (m, 2 H), 2.61 (dtt, J = 11, 7.0, 3.6 Hz, 1 H), 1.60 (d, J = 6.9 Hz, 3 H), 0.96 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H); HRMS(B) m/z 393.2029 (M + H)+.
Example 188 second eluted product (11 mg) 1H NMR (400 MHz, CD30D) 8 8.17 (d, J = .8 Hz, 1 H), 8.03 (s, 1 H), 7.68 — 7.62 (m, 3 H), 7.48 — 7.43 (m, 2 H), 7.37 (d, J = 5.8 Hz, 1 H), 7.32 — 7.27 (m, 1 H), 5.19 (q, J = 7.1 Hz, 1 H), 4.74 (dt, J = 8.5, 3.6 Hz, 1 H), 4.38 — 4.29 (m, 2 H), 2.37 — 2.33 (m, 1 H), 1.60 (d, J = 7.1 Hz, 3 H), 0.79 (d, J = 7.1 Hz, 3 H), 0.73 (s, J = 7.1 Hz, 3 H); HRMS(B) m/z 393.2039 (M + H)+.
Examples 189 and 190 A solution of (R)—3-(2-chloropyrimidinyl)—4-phenyloxazolidinone (97 mg, 0.35 mmol), 1-(biphenylyl)ethanamine hydrochloride (304 mg, 1.30 mmol, 3.7 equiv) and iPr2NEt (0.307 mL, 1.76 mmol, 5.0 equiv) in DMSO (1 mL) was heated at 110 °C for 1 1/2 h and at 130 °C for 20 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography /Heptane 10 to 50%) provided (R)—3-(2-((R)—1-(bipheny|— 4-yl)ethylamino)pyrimidinyl)—4-phenyloxazolidinone and (R)—3-(2-((S)—1-(biphenyl yl)ethylamino)pyrimidinyl)—4-phenyloxazolidinone.
Example 189 first eluted product (12 mg) 1H NMR (400 MHz, CD30D) 8 8.10 (d, J = 5.8 Hz, 1 H), 7.58 — 7.55 (m, 2 H), 7.44 — 7.37 (m, 6 H), 7.33 — 7.28 (m, 1 H), 7.24 — 7.14 (m, 6 H), 5.84 (dd, J = 8.6, 3.5 Hz, 1 H), 4.94 (q, J = 6.7 Hz, 1 H), 4.81 (t, J = 8.6 Hz, 1 H), 4.22 (dd, J = 8.8, 3.8 Hz, 1 H), 1.49 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 437.1981 (M + H)+.
Example 190 second eluted product (11 mg) 1H NMR (400 MHz, CD30D) 8 8.10 (d, J = .8 Hz, 1 H), 7.60 — 7.54 (m, 4 H), 7.44 — 7.28 (m, 11 H), 5.60 (dd, J = 8.6, 4.0 Hz, 1 H), 4.77 — 4.69 (m, 2 H), 4.19 (dd, J = 8.6, 4.0 Hz, 1 H), 1.25 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 437.1971 (M + H)+. es 191 and 192 “d O HNAN/ N/[ko E w o01>)“ (4S)—3-(2-(1-(2,3-dihydrobenzo[b][1,4]dioxinyl)ethylamino)pyrimidinyl) isopropyloxazolidinone le 130, 52 mg) was resolved on a column (IA 4.6 x 100 mm) using 40% iPrOH in C02 to give (S)—3-(2-((R)—1-(2,3-dihydrobenzo[b][1,4]dioxin yl)ethylamino)pyrimidinyl)isopropy|oxazolidinone and (2-((S)—1-(2,3- dihydrobenzo[b][1,4]dioxinyl)ethylamino)pyrimidinyl)isopropy|oxazolidinone.
Example 191 first eluted product (7 mg) 1H NMR (400 MHZ, CD30D) 8 8.10 (d, J = 5.6 Hz, 1 H), 7.33 — 7.31 (m, 1 H), 6.82 — 6.74 (m, 3 H), 4.88 (q, J = 7.1 Hz, 1 H), 4.58 — 4.53 (m, 1 H), 4.34 — 4.28 (m, 2 H), 4.21 — 4.18 (m, 4 H), 2.63 (td, J = 7.1, 3.5 Hz, 1 H), 1.47 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.86 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 385.1875 (M + H)+.
Example 192 second eluted product (19 mg) 1H NMR (400 MHz, CD30D) 8 8.12 (d, J = .8 Hz, 1 H), 7.33 — 7.31 (m, 1 H), 6.78 — 6.72 (m, 3 H), 4.93 (q, J = 6.7 Hz, 1 H), 4.68 — 4.64 (m, 1 H), 4.36 — 4.27 (m, 2 H), 2.08 (br s, 1 H), 1.47 (d, J = 7.1 Hz, 3 H), 0.76 (d, J = 7.1 Hz, 3 H), 0.65 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 385.1873 (M + H)+.
Examples 193 and 194 N \ 0 HN N NJk A solution of (R)—3-(2-chloropyrimidinyl)pheny|oxazolidinone (83 mg, 0.30 mmol) and 1-(3,4-dichlorophenyl)ethanamine (260 mg, 1.37 mmol, 4.5 equiv) in DMSO (1.5 mL) was heated at 110 °C for 1 1/2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)—3-(2-((R)—1-(3,4-dichlorophenyl)ethylamino)pyrimidinyl)—4-phenyloxazolidinone and (R)—3-(2-((S)—1-(3,4-dichlorophenyl)ethylamino)pyrimidinyl)—4-phenyloxazolidin one.
Example 193 first eluted product (13 mg) 1H NMR (400 MHz, CD30D) 8 8.11 (d, J = 5.6 Hz, 1 H), 7.44 — 7.38 (m, 5 H), 7.35 — 7.31 (m, 1 H), 7.27 — 7.25 (m, 2 H), 7.18 (dd, J = 8.3, 2.3 Hz, 1 H), 5.53 (dd, J = 8.8, 3.8 Hz, 1 H), 4.76 (t, J = 8.8 Hz, 1 H), 4.59 — 4.53 (m, 1 H), 4.18 (dd, J = 8.8, 4.3 Hz, 1 H), 1.22 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 429.0899 (M + H)+.
Example 194 second eluted product (26 mg) 1H NMR (400 MHz, CDgOD) 8 8.13 (d, J = .6 Hz, 1 H), 7.41 (d, J = 6.1 Hz, 1 H), 7.25 — 7.18 (m, 5 H), 7.09 — 7.06 (m, 2 H), 6.95 — 6.93 (m, 1 H), 5.78 (dd, J = 8.6, 3.5 Hz, 1 H), 4.89 (q, J = 6.7 Hz, 1 H), 4.79 (t, J = 8.6 Hz, 1 H), 4.18 (dd, J = 8.8, 3.8 Hz, 1 H), 1.42 (d. J = 7.1 Hz, 3 H); ) m/z 429.0887 (M + H)+.
Examples 195 and 196 HNAN/ $0“Ii OlD/LH (4S)—4-methylphenyl(2-(1-(4-(piperidiny|)phenyl)ethylamino)pyrimidin yl)oxazolidinone (example 141, 51 mg) was resolved on a column (IA 4.6 x 100 mm) using 45% MeOH in C02 to give (S)—4-methylphenyl(2-((S)—1-(4-(piperidin nyl)ethylamino)pyrimidinyl)oxazolidinone and (S)—4-methylphenyl(2- -(4-(piperidiny|)phenyl)ethylamino)pyrimidinyl)oxazolidinone.
Example 195 first eluted product (21.6 mg) 1H NMR (400 MHz, CDCI3) 8 8.13 (d, J = 5.8 Hz, 1 H), 7.41 (d, J = 5.8 Hz, 1 H), 7.36 — 7.33 (m, 4 H), 7.32 — 7.26 (m, 1 H), 6.88 — 6.82 (br m, 4 H), 5.01 (br s, 1 H), 4.30 (s, 2 H), 3.16 — 3.13 (m, 4 H), 2.20 (s, 3 H), 1.76 — 1.57 (br m, 6 H), 1.37 (d, J = 6.7 Hz, 3 H); HRMS(B) m/z 458.2558 (M + H)+.
Example 196 second eluted product (20.6 mg) 1H NMR (400 MHz, CDCI3) 8 8.14 (d, J = 5.8 Hz, 1 H), 7.50 — 7.27 (m, 6 H), 7.05 (d, J = 8.6 Hz, 2 H), 6.96 — 6.92 (br m, 2 H), 5.27 (br s, 1 H), 4.22 (s, 2 H), 3.21 — 3.13 (m, 4 H), 1.78 —1.76(br m, 7 H), 1.63 —1.57(br m, 2 H), 1.07 (d, J = 6.1 Hz, 3 H); HRMS(B) m/z 458.2559 (M + H)+.
Examples 197 and 198 4,4-dimethyl(2-(1-(4-(piperidiny|)phenyl)ethylamino)pyrimidinyl)oxazolidinone (example 183, 70 mg) was ed on a column (IA 4.6 x 100 mm) using 40% MeOH in C02 to give (S)—4,4-dimethyl(2-(1-(4-(piperidinyl)pheny|)ethylamino)pyrimidin yl)oxazolidinone and (R)—4,4-dimethyl(2-(1-(4-(piperidin yl)phenyl)ethylamino)pyrimidiny|)oxazolidinone.
Example 197 first eluted product (23.8 mg) 1H NMR (400 MHz, CDCI3) 8 8.17 (br d, J = .8 Hz, 1 H), 7.28 — 7.23 (m, 3 H), 6.93 (br d, J = 7.7 Hz, 2 H), 5.44 (br s, 1 H), 4.97 (br s, 1 H), 4.05 — 3.99 (m, 2 H), 3.15 — 3.12 (m, 4 H), 1.77 — 1.70 (m, 8 H), 1.61 — 1.54 (m, 5 H), 1.32 (br s, 2 H); ) m/z 396.2413 (M + H)+.
Example 198 second eluted product (22.3 mg) 1H NMR (400 MHz, CDCI3) 8 8.17 (br d, J = 5.5 Hz, 1 H), 7.28 — 7.23 (m, 3 H), 6.94 (br d, J = 7.5 Hz, 2 H), 5.48 (br s, 1 H), 4.97 (br s, 1 H), 4.05 — 3.99 (m, 2 H), 3.15 — 3.12 (m, 4 H), 1.77 — 1.70 (m, 8 H), 1.61 —1.54 (m, 5 H), 1.31 (br s, 2 H); HRMS(B) m/z 396.2410 (M + H)+.
Examples 199 and 200 A solution of (S)(2-chloropyrimidinyl)isopropy|oxazolidinone (98 mg, 0.41 mmol), 1-(1-(4-fluorophenyl)—1H-pyrazolyl)ethanamine hydrochloride (502 mg, 2.08 mmol, 5.1 equiv) and iPr2NEt (0.637 mL, 3.65 mmol, 9.0 equiv) in DMSO (1.5 mL) was heated at 110 °C for 16 h. The reaction mixture was d with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). ed cs were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 80%) provided (S)(2-((R)—1-(1-(4-f|uorophenyl)-1H-pyrazolyl)ethylamino)pyrimidinyl) isopropyloxazolidinone and (S)—3-(2-((S)—1-(1-(4-fluorophenyl)-1H-pyrazol yl)ethylamino)pyrimidinyl)isopropyloxazolidinone. e 199 first eluted product (49 mg) 1H NMR (400 MHZ, CD30D) 8 8.16 (d, J = 5.8 Hz, 1 H), 8.06 (s, 1 H), 7.71 — 7.67 (m, 3 H), 7.37 (d, J = 5.9 Hz, 1 H), 7.22 — 7.16 (m, 2 H), 5.20 (q, J = 6.6 Hz, 1 H), 4.74 (dt, J = 7.6, 3.8 Hz, 1 H), 4.40 — 4.34 (m, 2 H), 2.60 (dtd, J = 14, 7.0, 3.5 Hz, 1 H), 1.59 (d, J = 6.9 Hz, 3 H), 0.96 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 43 (M + H)+.
Example 200 second eluted product (27 mg) 1H NMR (400 MHz, CD30D) 8 8.17 (d, J = .8 Hz, 1 H), 8.00 (s, 1 H), 7.69 — 7.66 (m, 2 H), 7.61 (s, 1 H), 7.37 (d, J = 5.9 Hz, 1 H), 7.22 — 7.16 (m, 2 H), 5.19 (q, J = 6.7 Hz, 1 H), 4.73 (dt, J = 8.1, 3.5 Hz, 1 H), 4.39 — 4.30 (m, 2 H), 2.38 — 2.31 (m, 1 H), 1.59 (d, J = 6.8 Hz, 3 H), 0.79 (d, J = 7.1 Hz, 3 H), 0.73 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 411.1937 (M + H)+.
Examples 201 and 202 ”Ii 0 HNAN/ N/[ko / \\“‘\\/ ”\N l \\ A solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (93 mg, 0.38 mmol), 1-(1-(4-methoxyphenyl)—1H-pyrazolyl)ethanamine hydrochloride (514 mg, 2.03 mmol, 5.3 equiv) and iPr2NEt (0.605 mL, 3.46 mmol, 9.0 equiv) in DMSO (1.5 mL) was heated at 110 °C for 16 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 70%) provided (S)—4-isopropyl(2-((R)—1-(1-(4-methoxyphenyl)—1H-pyrazolyl)ethylamino)pyrimidin yl)oxazolidinone and (S)—4-isopropyl(2-((S)(1-(4-methoxyphenyl)—1H-pyrazol yl)ethylamino)pyrimidinyl)oxazolidinone.
Example 201 first eluted product (17 mg) 1H NMR (400 MHz, CD30D) 8 8.15 (d, J = 5.8 Hz, 1 H), 7.98 (s, 1 H), 7.63 (s, 1 H), 7.58 — 7.54 (m, 2 H), 7.37 (d, J = 5.8 Hz, 1 H), 7.03 — 6.99 (m, 2 H), 5.19 (q, J = 7.1 Hz, 1 H), 4.75 (dt, J = 7.7, 4.0 Hz, 1 H), 4.40 — 4.33 (m, 2 H), 3.83 (s, 3 H), 2.61 (dtd, J = 14, 7.1, 3.5 Hz, 1 H), 1.59 (d, J = 7.1 Hz, 3 H), 0.96 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 423.2138 (M + H)+.
Example 202 second eluted product (18 mg) 1H NMR (400 MHz, CDgOD) 8 8.16 (d, J = .8 Hz, 1 H), 7.91 (s, 1 H), 7.58 — 7.53 (m, 3 H), 7.37 (d, J = 5.9 Hz, 1 H), 7.03 — 6.99 (m, 2 H), 5.18 (q, J = 6.7 Hz, 1 H), 4.76 — 4.72 (m, 1 H), 4.39 — 4.30 (m, 2 H), 3.83 (s, 3 H), 2.31 (br s, 1 H), 1.59 (d, J = 7.1 Hz, 3 H), 0.80 (d, J = 7.1 Hz, 3 H), 0.73 (d, J = 7.1 Hz, 3 H); HRMS(B) m/z 423.214 (M + H)+. es 203 and 204 4-(4-methoxyphenyl)—5,5-dimethyl(2-((S)—1-phenylethylamino)pyrimidin yl)oxazolidinone (example 54, 62 mg) was resolved in on a column (AD-H 4.6 x 100 mm) with 30% MeOH modified with 0.2% Et2NH in C02 to give (S)—4-(4-methoxyphenyl)— ,5-dimethyl(2-((S)—1-phenylethylamino)pyrimidinyl)oxazolidinone and (R)—4-(4- methoxyphenyl)-5,5-dimethyl(2-((S)—1-phenylethylamino)pyrimidinyl)oxazolidin one.
Example 203 first eluted product (22 mg) 1H NMR (400 MHz, CDCI3) 8 8.12 (br d, J = 5.6 Hz, 1 H), 7.53 (d, J = 5.7 Hz, 1 H), 7.37 — 7.24 (m, 5 H), 7.08 — 7.05 (m, 2 H), 6.92 — 6.89 (m, 2 H), 5.47 (br s, 1 H), 5.02 (br s, 1 H), 4.66 (br s, 1 H), 3.83 (s, 3 H), 1.50 (s, 3 H), 1.28 (br d, J = 6.6 Hz, 3 H), 1.01 (s, 3 H); HRMS(B) m/z 419.208 (M + H)+.
Example 204 second eluted product (22.2 mg) 1H NMR (400 MHz, CDCI3) 8 8.11 (br d, J = 6.1 Hz, 1 H), 7.55 (d, J = 5.8 Hz, 1 H), 7.28 — 7.22 (m, 3 H), 7.08 (br s, 2 H), 7.01 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H), 5.40 (br s, 1 H), 5.30 (s, 1 H), 4.83 (br s, 1 H), 3.78 (s, 3 H), 1.66 (s, 3 H), 1.51 (d, J = 6.8 Hz, 3 H), 1.04 (s, 2 H); ) m/z 419.2083 (M + H)+.
Example 205 mo HNAN/ N’u\o 00* is” To a solution of tert-butyl 4-(4-((S)—1-(4-((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzyl)-2,2-dimethylpiperazine—1-carboxylate (78 mg, 0.14 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at -78 °C. The reaction was stirred at room temperature for 1 h then was concentrated and diluted with DCM (10 mL). The solution was stirred with 3 eq. of MP-carbonate resin (3.28 mmol/g, Biotage) for 1 h at room ature. The resin was removed by filtration and washed (2 x 5 mL) with DCM.
The filtrate was trated and purified through HPLC to give (2-(((S)—1-(4-((3,3- dimethylpiperaziny|)methyl)phenyl)ethyl)amino)pyrimidinyl)isopropy|oxazolidin one as a white solid (23 mg, 36% yield). 1H NMR (400 MHz, MeOD) 6 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 Hz, 1H), 7.26 — 7.18 (m, 4H), 5.00 (q, J = 6.9 Hz, 1H), 4.62 (br s, 1H), 4.36 — 4.16 (m, 2H), 3.36 (s, 2H), 2.81 (br t, J = 5.1 Hz, 2H), 2.30 (br s, 2H), 2.10 (br s, 2H), 1.82 (br s,1H), 1.45 (d, J = 7.0 Hz, 3H), 1.08 (s, 6H), 0.67 (br s, 3H), 0.52 (br s, 3H); HRMS(B) m/z 453.2969 (M + H)+.
Example 206 HNAN/iiN’U\o “00* a” A mixture of benzyl 4-(4-((S)(4-((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzyl)piperazinecarboxylate (190 mg, 0.34 mmol) and 10% Pd-C (40 mg, 0.038 mmol) in ethanol (3.4 ml) is stirred under 1 atmosphere pressure of hydrogen for 3 h. The mixture is filtered and concentrated to give (S)isopropy|(2-(((S)(4- aziny|methyl)phenyl)ethyl)amino)pyrimidinyl)oxazolidinone as a white solid (97 mg, 67.2% yield). 1H NMR (400 MHz, MeOD) 6 8.08 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 Hz, 1H), 7.28 — 7.19 (m, 4H), 5.01 (q, J = 7.0 Hz, 1H), 4.63 (br s, 1H), 4.37 — 4.14 (m, 2H), 3.44 (s, 2H), 2.78 (t, J = 5.0 Hz, 4H), 2.39 (br s, 4H), 1.89 (br s, 1H), 1.45 (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H), 0.52 (br s, 3H); HRMS(B) m/z 425.2662 (M + H)+.
Example 207 2012/055133 HNAN/“d NJLO In a 5 mL microwave vial a solution of (S)(2-((S)—1-(4- bromophenyl)ethylamino)pyrimidinyl)isopropyloxazolidinone (86 mg, 0.21 mmol), pyridinylboronic acid (26 mg, 0.21 mmol), Sodium bicarbonate (0.21 mL, 0.42 mmol, 2 M solution) in Dioxane (1 mL) was bubbled N2 for 3 min then Cl2Pd(dppf).CH2C|2 (17 mg, 0.021 mmol) was added. The capped tube was heated to 100°C for 16 h. After cooling the reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 10 mL).
Combined organics were dried over Na2804, filtered and concentrated. The crude material was ed through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to yield (S)isopropy(2-(((S)(4-(2-yl)phenyl)ethyl)amino)pyrimidin yl)oxazolidinone as a white solid (27 mg, 30.5% . 1H NMR (400 MHz, MeOD) 5 8.35 (d, J = 5.4 Hz, 1H), 8.08 (d, J = 5.9 Hz, 1H), 7.64 — 7.60 (m, 2H), 7.49 (br d, J = 1.8 Hz, 1H), 7.43 — 7.39 (m, 3H), 7.30 (d, J = 5.8 Hz, 1H), 5.02 (q, J = 6.8 Hz, 1H), 4.55 (br s, 1H), 4.27 — 4.18 (m, 2H), 2.52 (s, 3H), 1.65 (br s, 1H), 1.49 (d, J = 7.1 Hz, 3H), 0.55 (br s, 3H), 0.43 (br s, 3H); HRMS(B) m/z 418.2227 (M + H)+_ Example 208 ”'1 ° HNAN/ NJLO \‘LJ N.” I To a solution of tert-butyl 4-((S)isopropyloxooxazolidinyl)pyrimidinyl((S)—1-(4- (1-methyl-1H-pyrazolyl)phenyl)ethyl)carbamate (45 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL, 12 mmol) slowly at -78 °C. The reaction was d at room temperature for 1 h then was concentrated and diluted with DCM (10 mL). The solution was washed with saturated NaHCO3 on and brine. After separation, the aqueous phase was extracted with DCM (3 x 10 mL). Combined organics were dried over Na2804, filtered and concentrated to give (S)isopropyI(2-(((S)(4-(1-methyI-1H- pyrazolyl)phenyl)ethyl)amino)pyrimidinyl)oxazolidinone as a white solid (35 mg, 97% . 1H NMR (400 MHz, MeOD) 6 8.09 (d, J = 5.9 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.45 — 7.41 (m, 2H), 7.30 (d, J = 5.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 4.97 (q, J = 7.0 Hz, 1H), 4.58 (br s, 1H), 4.30 — 4.21 (m, 2H), 3.86 (s, 3H), 1.66 (br s, 1H), 1.48 (d, J = 7.0 Hz, 3H), 0.60 (br s, 3H), 0.48 (br s, 3H); HRMS(B) m/z 407.2179 (M + H)+.
Example209 IiN/lko 0100* a“ Following the above procedure for Example 208, N-(4-((S)(4-((S)isopropyl oxooxazolidinyl)pyrimidinylamino)ethy|)phenyl)cyclohexanecarboxamide was prepared as a white solid (45 mg, 92 % yield) from tert-butyl (S)(4- hexanecarboxamido)pheny|)ethyl(4-((S)isopropyIoxooxazolidiny|)pyrimidin- 2-yl)carbamate. 1H NMR (400 MHz, MeOD) 6 8.08 (d, J = 5.9 Hz, 1H), 7.47 — 7.41 (m, 2H), 7.30 (d, J = .8 Hz, 1H), 7.23 — 7.16 (m, 2H), 4.95 (q, J = 7.0 Hz, 1H), 4.60 (br s, 1H), 4.32 — 4.19 (m, 2H), 2.30 (tt, J = 11.8, 3.3 Hz, 1H), 1.89 — 1.72 (m, 4H), 1.72 — 1.63 (m, 1H), 1.54 — 1.39 (m, 5H), 1.39 — 1.14 (m, 4H), 0.67 (br s, 3H), 0.54 (br s, 3H); HRMS(B) m/z 452.2636 (M + H)+_ Example 210 oo HNAN/ N/U\o %J©* a” A solution of 4-((S)(4-((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzaldehyde (35 mg, 0.1 mmol) and 2-methyloctahydropyrrolo[3,4- c]pyrrole (14 mg, 0.11 mmol) in MeOH (2 mL) was added acetic acid (7.2 mg, 0.12 mmol) and 5-Ethylmethylpyridine borane complex (14 mg, 0.1 mmol, sigmaaldrich).
The solution was stirred at 50 °C for 4 h then 5 drops of water was added. The solution was stirred at room temperature for another 2 h then diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 10 mL). Combined organics were dried over Na2804, filtered and concentrated. The crude material was purified through HPLC to give (4S)—4-isopropyl (2-(((1S)—1-(4-((5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- y|)methyl)phenyl)ethyl)amino)pyrimidinyl)oxazolidinone as a white solid (10 mg, 21.7% yield). 1H NMR (400 MHz, MeOD) 6 8.07 (d, J = 5.8 Hz, 1H), 7.29 (d, J = 5.8 Hz, 1H), 7.25 — 7.20 (m, 4H), 5.00 (q, J = 7.0 Hz, 1H), 4.63 (br s, 1H), 4.31 — 4.23 (m, 2H), 3.55 — 3.48 (m, 2H), 2.68 (dh, J = 13.6, 4.3, 3.7 Hz, 2H), 2.64 — 2.48 (m, 4H), 2.36 — 2.29 (m, 4H), 2.28 (s, 4H), 1.84 (br s, 1H), 1.45 (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H), 0.52 (br s, 3H); HRMS(B) m/z 465.2975 (M + H)+.
Example 211 HN N N O "(3%NI A solution of 3-(2-fluoropyrimidinyl)oxazolidinone (89.1 mg, 0.487 mmol), 1-(3-(4- chlorophenyl)—1,2,4-oxadiazolyl)ethanamine (115.9 mg, 0.518 mmol, 1.06 equiv), and DIPEA (0.20 mL, 1.1 mmol, 2.4 equiv) in DMSO (1.5 mL) was heated at 110 0C for 100 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL).
After separation, the s phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over , filtered and concentrated. Silica gel column chromatography (MeOH in CH2C|2 0 to 5%) provided 1-(3-(4-chlorophenyl)-1,2,4- oxadiazolyl)ethylamino)pyrimidinyl)oxazolidinone (18.2 mg, white solid) in 10.3% yield. 1H NMR (400 MHz, s) 8.21 (br s, 1 H), 8.00 — 7.97 (m, 2 H), 7.65 — 7.61 (m, 2 H), 7.30 (br s, 1 H), 5,28 (br s, 1 H), 4.44 — 4.38 (br m, 2 H), 4.14 — 4.08 (m, 1 H), 3.99 (br S, 0.5 H), 3.75 (br S, 0.5 H), 1.64 (d, J = 7.0 Hz, 3 H); HRMS(B) m/z 387.0962 (M + Example 212 A solution of (4-phenoxyphenyl)ethanamine hydrochloride (281mg, mol), 3- (2-chlorofluoropyrimidinyl)oxazolidinone (103mg, 0.379mmol) and DIPEA (0.331ml, 1.896mmol) in DMSO was heated to 110°C for 1h. LCMS showed little product. Heated for an additional 16h. LCMS still showed starting material. Added an additional 5 equivalents of DIPEA and 1 equivalent of KF. Heated to 110°C for 2h. LCMS shows product. The reaction e was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 8 mL). Combined organics were dried over Na2804, filtered and concentrated. Purified by column chromatography (10% to 50% EtOAc/Heptane) to give (S)(5-f|uoro(1-(4- phenoxyphenyl)ethylamino) pyrimidinyl)—3-oxaazaspiro[4.4]nonanone (62mg, 0.138mmol). 1H NMR (400 MHz, MeOD) 5 8.25 (d, J = 2.8 Hz, 1H), 7.34 (ddd, J = 8.7, 4.9, 2.3 Hz, 4H), 7.16 — 7.04 (m, 1H), 7.02 — 6.90 (m, 4H), 4.96 (q, J = 7.0 Hz, 1H), 4.30 — 4.25 (m, 2H), 2.38 (dt, J = 13.1, 8.4 Hz, 1H), 2.02 (br s, 1H), 1.80 (ddd, J = 12.7, 7.3, 4.2 Hz, 1H), 1.71 — 1.63 (br m, 2H), 1.61 — 1.49 (m, 3H), 1.53 (d, J = 7.0 Hz, 3 H). ) (M+H) 449.1984 Calc’d (M+H) 449.1989 The compounds in Table 7 were prepared using methods substantially similar to those bed for the preparation of Examples 1, 113, 211 and 212.
Table 7.
WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 WO 46136 2012/055133 Table 8. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 7.
Example: Name 1H NMR (400 MHz, CD30D) 8 ppm (other LCMS solvents described 213: (S)(2- 8.08 (d, J = 5.8 Hz, 1 H), 7.33 (d, J = 5.8 HRMS(B) ((cyclohexylmethyl)amino) Hz, 1 H), 4.80 - 4.78 (m, 1 H), 4.42 - 4.37 m/z pyrimidinyl)—4- (m, 2 H), 3.24 (dd, J = 13, 6.3 Hz, 1 H), 319.2132 isopropyloxazolidinone 3.10 (dt, J = 13, 6.8 Hz, 1 H), 2.88 - 2.80 (M + H)+ (m, 1 H), 1.82- 1.58 (m, 7 H), 1.31 - 1.18 (m, 4 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3 H - 214: (R)—3-(2-(((S)—1-(4- 8.46 (d, J = 5.8 Hz, 1H), 7.85 — 7.73 (m, HRMS(B) bromophenyl)ethyl)amino) 5H), 7.73 — 7.87 (m, 1H), 7.84 (dd, J = 7.1, m/z pyrimidinyl)—4- 1.8 Hz, 2H), 7.58 — 7.52 (m, 2H), 5.92 (dd, 439.0762 phenyloxazolidinone J = 8.8, 4.0 Hz, 1H), 5.13 (t, J = 8.7 Hz, M+ 1H), 4.98 (d, J = 7.0 Hz, 1H), 4.55 (dd, J = 8.7, 4.0 Hz, 1H , 1.58 d, J = 7.0 Hz, 3H - 215: (S)(2-(((S)—1-(4- 8.38 (s, 1H), 8.07 (d, J = 5.9 Hz, 1H), 7.30 HRMS(B) ((5,6-dihydro- (d, J = 8.0 Hz, 1H), 7.28 (s, 4H), 5.03 (q, J m/z [1 ,2,4]triazolo[4,3- = 7.0 Hz, 1H), 4.83 (br s, 1H), 4.31 — 4.23 67 a]pyrazin-7(8H)— (m, 2H), 4.08 (t, J = 5.5 Hz, 2H), 3.78 — (M + H)+ yl)methyl)phenyl)ethyl)ami 3.69 (m, 4H), 2.89 (td, J = 5.4, 2.1 Hz, 2H), no)pyrimidinyl)—4- 1.80 (br s, 1H), 1.48 (d, J = 7.0 Hz, 3H), p lidinone 0.68 brs, 3H , 0.53 brs, 3H 216: (S)(2-(((S)—1-(3- 8.04 (d, J = 5.9 Hz, 1H), 7.38 — 7.15 (m, ) fluoro((3,3,4- 2H), 7.02 (dd, J = 7918 Hz, 1H), 6.94 m/z trimethylpiperazin (dd, J =11.0, 1.8 Hz, 1H), 4.95 (q, J = 7.0 485.3107 yl)methyl)phenyl)ethyl)ami Hz, 1H), 4.58 (brs, 1H), 4.32 —4.11 (m, (M + H)+ no)pyrimidinyl)—4- 2H), 3.38 (br s, 2H), 2.46 (br t, J = 4.9 Hz, pyloxazolidinone 2H), 2.32 (br s, 2H), 2.14 (br s, 2 H), 2.10 (s, 3H), 1.73 (br s, 1H), 1.40 (d, J = 7.1 Hz, 3H), 0.95 (s, 3H), 0.95 (s, 3H), 0.63 (br s, 3H , 0.49 brs, 3H 217: (S)(2-(((S)—1-(3- 8.09 (d, J = 6.0 Hz, 1H), 7.41 — 7.20 (m, HRMS(B) fluoro((4- 2H), 7.11 (dd, J = 781.7 Hz, 1H), 7.04 m/z methylpiperazin (dd, J =11.0, 1.8 Hz,1H),5.01 (q, J = 7.0 457.2699 yl)methyl)phenyl)ethyl)ami Hz, 1H), 4.63 ( br s, 1H), 4.38 — 4.18 (m, (M + H)+. no)pyrimidinyl)—4- 2H), 3.57 (s, 2H), 2.82 (br s, 4H), 2.80 (br isopropyloxazolidinone s, 4H), 2.51 (s, 3H), 1.83 (brs, 1H), 1.45 (d, J = 7.1 Hz, 3H), 0.69 (s, 3H), 0.54 (s, 218: (4S)—3-(2-(((1S)—1-(4- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) ((3,5-dimethylpiperazin Hz, 1H), 7.28 — 7.19 (m, 4H), 5.01 (q, J = m/z yl)methyl)phenyl)ethyl)ami 7.0 Hz, 1H), 4.63 (br s, 1H), 4.34 — 4.18 453.2971 no)pyrimidinyl)—4- (m, 2H), 3.46 — 3.39 (m, 2H), 2.89 — 2.76 (M + H)+ isopropyloxazolidinone (m, 2H), 2.76 — 2.67 (m, 2H), 1.82 (br s, 1H), 1.59 (t, J = 10.9 Hz, 2H), 1.45 (d, J = 7.0 Hz, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.68 br s, 3H , 0.52 br s, 3H 219: (S)isopropyl(2- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.9 HRMS(B) (((S)(4-((4-methyl-1,4- Hz, 1H), 7.28 — 7.24 (m, 4H), 5.02 (q, J = m/z diazepan 7.0 Hz, 1H), 4.63 (br s, 1H), 4.35 — 4.22 453.2968 yl)methyl)phenyl)ethyl)ami (m, 2H), 3.67 — 3.59 (m, 2H), 3.09 — 3.07 (M + H)+ no p rimidin m, 2H , 2.99 dd, J = 6.2, 3.5 Hz, 2H y|)oxazo|idinone 2.79 — 2.77 (m, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.63 (s, 3H), 1.93 — 1.87 (m, 3H), 1.80 (br s, 1H), 1.45 (d, J = 7.0 Hz, 3H), 0.69 (br s, 3H , 0.54 br s, 3H 220: (S)(2-(((S)(4- 8.07 (d, J = 5.9 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) ert-butyl)piperazin Hz, 1H), 7.24 (q, J = 8.2 Hz, 4H), 5.01 (q, J m/z y|)methyl)phenyl)ethy|)ami = 6.9 Hz, 1H), 4.63 (br s, 1H), 4.31 — 4.24 481.3283 no)pyrimidiny|) (m, 2H), 3.49 — 3.42 (m, 2H), 2.60 (br s, (M + H)+ isopropyloxazolidinone 4H), 2.46 (br s, 4H), 1.76 (br s, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.03 (s, 9H), 0.69 (s, 3H , 0.53 s, 3H 221: (S)isopropy|—3-(2- 8.08 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) 1-(4-((3,3,4- Hz, 1H), 7.26 — 7.18 (m, 4H), 5.01 (q, J = m/z trimethylpiperazin 7.0 Hz, 1H), 4.63 (br s, 1H), 4.31 — 4.24 467.3127 y|)methyl)phenyl)ethy|)ami (m, 2H), 3.37 (s, 2H), 2.54 (br t, J = 5.0 Hz, (M + H)+ no)pyrimidin 2H), 2.38 (br s, 2H), 2.17 (s, 3H),2.14 (br s, y|)oxazo|idinone 2H), 1.85 (br s, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.01 (s, 6H), 0.68 (br s, 3H), 0.53 (br 222: (S)isopropy|—3-(2- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) (((S)(4-((4- Hz, 1H), 7.24 (q, J = 8.3 Hz, 4H), 5.01 (q, J m/z isopropylpiperazin = 7.0 Hz, 1H), 4.63 (br s, 1H), 4.31 — 4.24 467.3120 y|)methyl)phenyl)ethy|)ami (m, 2H), 3.46 (s, 2H), 2.63 — 2.44 (m, 9H), (M + H)+ no)pyrimidin 1.84 (br s, 1H), 1.45 (d, J = 7.1 Hz, 3H), y|)oxazo|idinone 1.02 (d, J = 6.5 Hz, 6H), 0.68 (br s, 3H), 0.53 br s, 3H 223: (4S)—3-(2-(((1S)—1-(4- 8.07 (d, J = 5.9 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) ((3,4-dimethylpiperazin Hz, 1H), 7.23 (q, J = 8.1 Hz, 4H), 5.01 (q, J m/z y|)methyl)phenyl)ethy|)ami = 7.0 Hz, 1H), 4.63 (br s, 1H), 4.35 — 4.20 60 no)pyrimidiny|) (m, 2H), 3.51 — 3.35 (m, 2H), 2.82 — 2.61 (M + H)+ isopropyloxazolidinone (m, 3H), 2.36 — 2.24 (m, 1H), 2.23 (s, 3H), 2.20 — 2.08 (m, 2H), 1.89 — 1.80 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H , 0.68 br s, 3H ,0.52 br s, 3H 224: (S)(2-(((S)(4- 8.08 (d, J = 5.8 Hz, 1H), 7.31 (d, J = 5.8 HRMS(B) ((4,4-difluoropiperidin Hz, 1H), 7.25 (q, J = 8.2 Hz, 4H), 5.02 (q, J m/z y|)methyl)phenyl)ethy|)ami = 7.0 Hz, 1H), 4.63 (br s, 1H), 4.32 — 4.24 14 no)pyrimidinyl)—4- (m, 2H), 3.51 (s, 2H), 2.52 (br t, J = 5.8 Hz, (M + H)+ isopropyloxazolidinone 4H), 1.98 — 1.87 (m, 4H), 1.81 (br s, 1H), 1.46 (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H), 0.52 br s, 3H 225: 2-fluoro—4-((S)—1-((4- 8.09 (d, J = 5.7 Hz, 1H), 7.58 (t, J = 7.7 Hz, ) ((S)isopropy|—2- 1H), 7.33 (d, J = 5.8 Hz, 1H), 7.20 (dd, J = m/z oxooxazolidin 7.9, 1.6 Hz, 1H), 7.13 (dd, J = 12.1, 1.7 Hz, 568.2549 y|)pyrimidin 1H), 5.03 (q, J = 7.0 Hz, 1H), 4.61 (br s, (M + H)+ y|)amino)ethy|)—N-(4- 1H), 4.31 — 4.24 (m, 2H), 3.97 — 3.80 (m, (2,2,2- 3H), 3.65 (dt, J = 4.7, 2.3 Hz, 1H), 1.90 (dt, trifluoroethoxy)cyc|ohexy|) J = 12.5, 4.0 Hz, 2H), 1.72 — 1.58 (m, 6H), benzamide 1.47 (d, J = 7.0 Hz, 3H), 0.68 (br s, 3H), 0.56 br s, 3H 226: 2-fluoro—N-(4- 8.09 (d, J = 6.0 Hz, 1H), 7.58 (t, J = 7.7 Hz, HRMS(B) hydroxy 1H), 7.33 (d, J = 5.8 Hz, 1H), 7.20 (dd, J = m/z methylcyclohexyl)((S)- 8.0, 1.6 Hz, 1H), 7.13 (dd, J = 12.0, 1.7 Hz, 500.2589 1-((4-((S)isopropy|—2- 1H), 5.03 (q, J = 7.0 Hz, 1H), 4.61 (br s, (M + H)+ oxooxazolidin 1H ,4.31 — 4.25 m, 2H , 3.89 dt, J = 9.4, WO 46136 y|)pyrimidin-2— 4.7 Hz, 1H), 1.95 —1.82(m,2H), 1.75 — y|)amino)ethy|)benzamide 1.49 (m, 7H), 1.47 (d, J = 7.0 Hz, 3H), 1.21 s, 3H ,0.68 brs, 3H , 0.56 brs, 3H 227: -(2-(((1S)—1-(3- 8.09 (d, J = 5.8 Hz, 1H), 7.32 (d, J = 5.8 HRMS(B) fluoro—4- Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.10 (dd, m/z ((hexahydropyrrolo[1,2— J = 7.918 Hz, 1H), 7.03 (dd, J =11.0,1.8 483.2878 a]pyrazin-2(1H)— Hz, 1H), 5.00 (q, J = 7.0 Hz, 1H), 4.63 (br (M + H)+ y|)methyl)phenyl)ethy|)ami s, 1H), 4.31 — 4.24 (m, 2H), 3.62 — 3.53 (m, no)pyrimidinyl)—4- 2H), 2.98 — 2.91 (m, 3H), 2.80 — 2.75 (m, isopropyloxazolidinone 1H), 2.34 — 2.18 (m, 2H), 2.18 — 2.01 (m, 2H), 1.90 (t, J = 10.4 Hz,1H),1.83 —1.65 (m, 4H), 1.45 (d, J = 7.0 Hz, 3H), 1.36 — 1.27 (m, 1H), 0.68 (br s, 3H), 0.54 (br s, 228: (S)(2-((S)—1-(4-((4- 8.07 (d, J = 5.9 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) cyclopropylpiperazin Hz, 1H), 7.23 (q, J = 8.0 Hz, 4H), 5.01 (q, J m/z y|)methyl)phenyl)ethylami = 7.0 Hz, 1H), 4.62 (br s, 1H), 4.35 — 4.19 465.2975 imidinyl)—4- (m, 2H), 3.45 (s, 2H), 2.62 (br s, 4H), 2.41 (M + H)+ isopropyloxazolidinone (br s, 4H), 1.79 (br s, 1H), 1.65 — 1.56 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H), 0.67 (br s, 3H), 0.52 (br s, 3H), 0.45 — 0.38 (m, 2H), 0.38 — 0.29 m, 2H 229: (2-((S)—1-(4-((4- 8.08 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.2 HRMS(B) cyclobutylpiperazin Hz, 1H), 7.47 — 7.24 (m, 4H), 5.28 — 5.06 m/z y|)methyl)phenyl)ethylami (m, 1H), 4.66 (q, J = 4.8, 4.4 Hz, 1H), 4.34 479.3165 imidinyl)—4- (d, J = 5.7 Hz, 2H), 3.91 (s, 2H), 3.61 (p, J (M + H)+ isopropyloxazolidinone = 8.3 Hz, 1H), 3.20 (br s, 4H), 3.02 (br s, 4H), 2.32 — 2.04 (m, 4H), 1.90 — 1.66 (m, 3H), 1.52 (d, J = 7.0 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H , 0.54 d, J = 6.7 Hz, 3H 230: (4S)—3-(2-((1S)—1-(4- 8.07 (d, J = 5.8 Hz, 1H), 7.34 — 7.19 (m, HRMS(B) ((dihydro—1H-pyrido[1,2— 5H), 5.01 (q, J = 7.0 Hz, 1H), 4.63 (br s, m/z a]pyrazin- 1H), 4.33 — 4.22 (m, 2H), 3.49 — 3.39 (m, 479.3131 2(6H,7H,8H,9H,9aH)— 2H), 2.83 — 2.71 (m, 2H), 2.66 (dq, J = (M + H)+ y|)methyl)phenyl)ethylami 11.0, 2.2 Hz, 2H), 2.32 — 2.14 (m, 2H), no)pyrimidinyl)—4- 2.09 — 1.94 (m, 2H), 1.82 (t, J = 10.8 Hz, isopropyloxazolidinone 1H), 1.70 (dt, J = 12.4, 3.5 Hz, 1H), 1.64 — 1.50 (m, 2H), 1.48 — 1.39 (m, 5H), 1.35 — 1.21 (m, 1H), 1.14 (tdd, J = 13.0, 10.8, 3.6 Hz, 1H , 0.68 br s, 3H ,0.52 br s, 3H 231: (4S)—4-isopropy|—3-(2— 8.07 (d, J = 5.9 Hz, 1H), 7.36 — 7.21 (m, HRMS(B) ((1S)—1-(4-((3-methy|—3,8- 5H), 5.01 (q, J = 7.0 Hz, 1H), 4.62 (br s, m/z diazabicyclo[3.2.1]octan- 1H), 4.33 — 4.21 (m, 2H), 3.45 (s, 2H), 3.07 465.2964 8- (qd, J = 4.6, 4.2, 1.9 Hz, 2H), 2.63 — 2.50 (M + H)+ y|)methyl)phenyl)ethylami (m, 2H), 2.25 (ddd, J = 10.7, 4.4, 1.8 Hz, no)pyrimidin 2H), 2.15 (s, 3H), 2.04 — 1.93 (m, 2H), 1.83 y|)oxazolidin-2—one — 1.72 (m, 3H), 1.45 (d, J = 7.0 Hz, 3H), 0.67 br s, 3H , 0.51 br s, 3H 232: (4S)—4-isopropy|—3-(2— (CDCI3) 8.17 (d, J = 5.7 Hz, 1H), 7.42 (d, J HRMS(B) ((1S)—1-(4-((8-methy|—3,8- = 5.7 Hz, 1H), 7.23 (s, 4H), 5.46 (br s, 1H), m/z diazabicyclo[3.2.1]octan- 5.01 (br s, 1H), 4.60 (dt, J = 6.9, 3.3 Hz, 465.2963 3- 1H), 4.28 (t, J = 8.7 Hz,1H),4.21 (dd, J = (M + H)+ y|)methyl)phenyl)ethylami 9.1, 3.1 Hz, 1H), 3.42 (d, J = 1.7 Hz, 2H), no)pyrimidin 3.10 — 2.96 (m, 2H), 2.58 — 2.48 (m, 2H), | oxazolidin-2—one 2.33 — 2.18 m, 5H — 1.84 , 2.06 m, 3H 1.81 (dd, J = 7.8, 4.4 Hz, 2H), 1.52 (d, J = 6.8 Hz, 3H , 0.71 brs, 3H , 0.64 brs, 3H 233: (4S)—3-(2-((1S)—1-(4- 8.12 (d, J = 5.8 Hz, 1H), 7.34 (d, J = 5.8 HRMS(B) ((hexahydropyrrolo[1,2- Hz, 1H), 7.33 — 7.24 (m, 4H), 5.05 (q, J = m/z a]pyrazin-2(1H)— 7.0 Hz, 1H), 4.67 (br s, 1H), 4.38 — 4.26 465.2972 hyl)pheny|)ethylami (m, 2H), 3.64 — 3.49 (m, 2H), 3.11 — 3.00 (M + H)+ imidinyl)—4- (m, 2H), 2.96 (br d, J = 11.0 Hz, 1H), 2.83 isopropyloxazolidinone (br d, J = 11.2 Hz, 1H), 2.45 — 2.34 (m, 1H), 2.32— 2.25 (m, 3H), 1.94 (t, J = 10.5 Hz, 1H), 1.88 — 1.77 (m, 4H), 1.49 (d, J = 7.0 Hz, 3H), 1.47 — 1.35 (m, 1H), 0.72 br 234: (S)(2-(((S)—1-(2H- HRMS(B) tetrazoIyl) ethyl) amino) m/z pyrimidinyl)—4- 319.1624 isopropyloxazolidinone (M+H )+, RT=1.33 min. 235: benzyl 4-(4-((S)—1-(4- 8.07 (d, J = 5.8 Hz, 1H), 7.34 — 7.18 (m, HRMS(B) ((S)isopropy|—2- 10H), 5.05 (s, 2H), 5.01 (q, J = 6.9 Hz, m/z oxooxazolidin 1H), 4.62 (br s, 1H), 4.32 — 4.18 (m, 2H), 559.3026 y|)pyrimidin 3.49 — 3.34 (m, 4H), 3.46 (s, 2H), 2.36 (t, J (M + H)+ ylamino)ethy|)benzy|)piper = 5.1 Hz, 4H), 1.75 (brs, 1H), 1.45 (d, J = azine—1-carbox late 7.0 Hz, 3H , 0.66 br s, 3H , 0.50 br s, 3H 236: (S)(2-((S)—1-(4-((4- 8.07 (d, J = 5.8 Hz, 1H), 7.30 (d, J = 5.8 HRMS(B) aminomethylpiperidin- Hz, 1H), 7.27 — 7.21 (m, 4H), 5.01 (q, J = m/z 1- 7.0 Hz, 1H), 4.63 (br s, 1H), 4.34 — 4.18 453.2972 y|)methyl)pheny|)ethylami (m, 2H), 3.53 — 3.40 (m, 2H), 2.59 — 2.21 (M + H)+ no)pyrimidinyl)—4- (br m, 4H), 1.78 (br s, 1H), 1.52 (ddt, J = isopropyloxazolidinone 11.8, 8.7, 5.2 Hz, 4H), 1.45 (d, J = 7.0 Hz, 3H), 1.07 (s, 3H), 0.67 (br s, 3H), 0.51 (br s, 3H 237: (S)(2-((S)—1-(4-((4- (CDCI3) 8.17 (d, J = 5.7 Hz, 1H), 7.42 (d, J HRMS(B) (dimethylamino)piperidin- = 5.7 Hz, 1H), 7.25 (d, J = 8.2 Hz, 4H), m/z 1- 5.43 (br s, 1H), 5.01 (br s, 1H), 4.60 (dt, J 467.3121 y|)methyl)pheny|)ethylami = 8.6, 3.3 Hz, 1H), 4.28 (t, J = 8.7 Hz, 1H), (M + H)+ no)pyrimidinyl)—4- 4.21 (dd, J = 9.1, 3.2 Hz, 1H), 3.44 (s, 2H), isopropyloxazolidinone 2.89 (dp, J = 11.5, 2.8 Hz, 2H), 2.26 (s, 6H), 2.11 (tt, J = 11.3, 3.6 Hz, 1H), 1.93 (td, J = 11.9, 2.4 Hz, 2H), 1.90 (br s, 1H), 1.75 (dq, J = 12.0, 2.8 Hz, 2H), 1.60 — 1.43 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 0.70 (br s, 3H , 0.63 br s, 3H 238: (S)(2-((S)—1-(4- ) 5 8.18 (dd, J = 5.8, 1.3 Hz, 1H), HRMS(B) ((tert- 7.44 (dd, J = 5.7, 1.2 Hz, 1H), 7.37 — 7.22 m/z butylamino)methy|)pheny|) (m, 5H), 5.52 (br s, 1H), 5.15 — 4.95 (m, 01 ethylamino)pyrimidiny|)- 1H), 4.70 — 4.55 (m, 1H), 4.30 (td, J = 8.8, (M + H)+ 4-isopropyloxazolidin 2.1 Hz, 1H), 4.23 (dd, J = 9.1, 3.0 Hz,1H), one 3.71 (d, J = 2.0 Hz, 2H), 2.06 (s, 1H), 1.54 (dd, J = 7.1,1.9 Hz, 3H), 1.18 (sm, 9H), 0.85 — 0.59 m, 6H ' 239: N-tert-butyI((S) (CDCI3) 5 8.16 (dd, J = 5.8, 1.2 Hz, 1H), ) (4-((S)isopropy|—2- 7.66 (d, J = 8.3 Hz, 2H), 7.43 (dd, J = 5.8, m/z oxooxazolidin 0.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 5.88 426.2488 | p rimidin y|amino)ethy|)benzamide 4.55 (br s, 1H), 4.26 (t, J = 8.7 Hz, 1H), 4.19 (dd, J = 9.2, 3.2 Hz, 1H), 1.53 (d, J = , 1.45 s, 9H , 0.84 m, 8H 240: N-cyclohexyI((S)- (CDCI3) 5 8.17 (d, J = 5.7 Hz, 1H), 7.89 (d, HRMS(B) 1-(4-((S)—4-isopropy|—2- J = 8.1 Hz, 2H), 7.44 (d, J = 5.8 Hz,1H), m/z oxooxazolidin 7.38 (d, J = 7.9 Hz, 2H), 5.91 (d, J = 8.3 452.2640 imidin Hz, 1H), 5.51 (brs, 1H), 5.04 (brs, 1H), (M + H)+ y|amino)ethy|)benzamide 4.53 (br s, 1H), 4.26 (t, J = 8.7 Hz, 1H), 4.19 (dd, J = 9.1, 3.2 Hz, 1H), 4.04 — 3.89 (m, 1H), 2.07 — 1.95 (m, 2H), 1.74 (dp, J = 11.5, 3.8 Hz, 2H), 1.84 (tt, J = 7.4, 3.7 Hz, 2H), 1.54 (d, J = 8.9 Hz, 3H), 1.42 (qt, J = 12.4, 3.5 Hz, 2H), 1.30 — 1.17 (m, 3H), 0.84 brs, 8H 241: 4-((S)(4-((S)—4- (CDCI3) 5 8.19 (d, J = 5.8 Hz, 1H), 7.83 (d, HRMS(B) isopropyIoxooxazolidin- J = 8.2 Hz, 2H), 7.77 (s, 1H), 7.88 — 7.59 m/z 3-y|)pyrimidin (m, 2H), 7.48 — 7.41 (m, 3H), 7.37 (dd, J = 446.2170 y|amino)ethy|)—N- 8.5, 7.3 Hz, 2H), 7.22 — 7.11 (m, 1H), 5.48 (M + H)+ benzamide (br s, 1H), 5.08 (br s, 1H), 4.58 (br s, 1H), 4.27 (t, J = 8.7 Hz, 1H), 4.20 (dd, J = 9.2, 3.2 Hz, 1H), 1.57 (t, J = 5.8 Hz, 3H), 0.85 242: (S)isopropy|—3-(2- (CDCI3) 5 8.18 (d, J = 5.7 Hz, 1H), 7.45 (d, HRMS(B) ((S)—1-(4-(piperidine—1- J = 5.7 Hz, 1H), 7.33 (s, 4H), 5.45 (br s, m/z carbonyl)pheny|)ethylamin 1H), 5.05 (br s, 1H), 4.59 (dt, J = 7.3, 2.9 92 o)pyrimidin Hz, 1H), 4.27 (t, J = 8.7 Hz, 1H), 4.21 (dd, (M + H)+ y|)oxazo|idinone J = 9.1, 3.2 Hz, 1H), 3.51 (d, J = 141.8 Hz, 4H), 1.80 (dd, J = 52.4, 5.9 Hz, 10H), 0.88 d, J = 25.5 Hz, 8H - 243: (S)isopropy|—3-(2- (CDCI3) 5 8.18 (d, J = 5.7 Hz, 1H), 7.45 (d, HRMS(B) ((S)(4-(4- J = 5.7 Hz, 1H), 7.35 (s, 4H), 5.42 (br s, m/z methylpiperazine—1 - 1H), 5.05 (br s, 1H), 4.58 (br s, 1H), 4.28 453.2611 carbonyl)pheny|)ethylamin (t, J = 8.8 Hz, 1H), 4.21 (dd, J = 9.2, 3.1 (M + H)+ o)pyrimidin Hz, 1H), 3.78 (br s, 2H), 3.44 (br s, 2H), y|)oxazo|idinone 2.53 — 2.39 (m, 2H), 2.32 (s, 4H), 1.85 (m, 2H), 1.53 (d, J = 8.9 Hz, 3H), 0.82 — 0.50 244: (S)isopropy|—3-(2- (CDCI3) 5 8.18 (d, J = 5.7 Hz, 1H), 7.42 (d, HRMS(B) ((S)—1-(4-(piperidin-1 - J = 5.7 Hz, 1H), 7.24 (s, 4H), 5.58 (br s, m/z y|methyl)phenyl)ethylamin 1H), 5.15 — 4.85 (m, 1H), 4.80 (dt, J = 8.4, 424.2704 o)pyrimidin 3.4 Hz, 1H), 4.27 (t, J = 8.7 Hz, 1H), 4.20 (M + H) + y|)oxazo|idinone (dd, J = 9.1, 3.2 Hz, 1H), 3.43 (s, 2H), 2.54 — 2.22 (m, 4H), 1.99 (br s,1H), 1.81 — 1.48 (m, 7H), 1.42 (q, J = 8.8, 8.0 Hz, 2H), 0.88 245: (S)isopropy|—3-(2- ) 5 8.18 (d, J = 5.7 Hz, 1H), 7.45 (d, HRMS(B) ((S)(4- J = 5.7 Hz, 1H), 7.28 (s, 4H), 5.58 (br s, m/z (morpholinomethyl)pheny| 1H), 5.18 — 4.94 (m, 1H), 4.83 (dt, J = 7.8, 87 )ethylamino)pyrimidin 3.5 Hz, 1H), 4.30 (t, J = 8.8 Hz, 1H), 4.23 (M + H) + y|)oxazo|idinone (dd, J = 9.0, 3.1 Hz, 1H), 3.72 (t, J = 4.8 Hz, 4H), 3.49 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H), 2.19 — 1.82 (m, 1H), 1.55 (d, J = 8.9 Hz, 3H — 0.48 , 0.90 m, 8H - 246: (S)isopropy|—3-(2- (CDCI3) 5 8.17 (d, J = 5.8 Hz, 1H), 7.43 (d, HRMS(B) S 4- 4- J = 5.8 Hz, 1H 7.27 , d, J = 8.2 Hz, 4H m/z methylpiperazin 5.52 (br s, 1H), 5.03 (br s, 0H), 4.62 (dt, J 439.2801 y|)methyl)pheny|)ethylami = 8.5, 3.4 Hz, 1H), 4.29 (t, J = 8.7 Hz, 1H), (M + H) + no)pyrimidin 4.22 (dd, J = 9.1, 3.2 Hz, 1H), 3.48 (s, 2H), y|)oxazo|idinone 2.48 (br s, 9H), 2.30 (s, 3H), 1.54 (d, J = 8.9 Hz, 3H — 0.57 , 0.97 m, 8H - 247: (R)—4-(4- (CDCI3) 5 8.18 (d, J = 5.8 Hz, 1 H), 7.41 (d, HRMS(B) fluoropheny|)methyI J = 5.8 Hz, 1 H), 7.33 — 7.29 (m, 2 H), 7.25 m/z (2-((S) — 7.20 (m, 3 H), 7.15 — 7.08 (m, 4 H), 5.17 393.1726 ethylamino)pyrimidi (br s, 1 H), 4.21 (br s, 1 H), 4.20 — 4.15 (m, (M + H)+. )oxazo|idinone 2 H), 1.81 (s, 3 H), 1.21 (d, J = 7.1 Hz, 3 248: (S)(2-(1- (CDCI3) 6 8.19 (d, J = 5.8 Hz, 1 H), 7.37 — HRMS(B) phenylethylamino)pyrimidi 7.33 (m, 4 H), 7.29 — 7.24 (m, 2 H), 5.39 m/z ny|)oxa (br s, 1 H), 5.12 — 5.05 (m, 1 H), 4.09 — 339.1805 azaspiro[4.4]nonanone 4.05 (m, 2 H), 2.83 — 2.75 (m, 1 H), 2.35 (M + H)+ (br s, 1 H), 1.95— 1.86 (m, 1 H), 1.71 (br s, 1 H), 1.67 — 1.61 (m, 2 H), 1.58 (d, J = 7.0 , 1.45 br s, 2 H 249: (R)—4-(4- ) 6 8.18 (d, J = 5.8 Hz, 1 H), 7.42 (d, HRMS(B) fluoropheny|)methyI J = 5.8 Hz, 1 H), 7.38 — 7.33 (m, 2 H), 7.26 m/z (2-((S)(4- — 7.22 (m, 2 H), 7.14 — 7.06 (m, 5 H), 7.00 485.1979 phenoxyphenyl)ethy|amin — 6.94 (m, 4 H), 5.21 (br s, 1 H), 4.23 — (M + H)+ o)pyrimidin 4.17 (m, 3 H), 1.71 (br s, 3 H), 1.20 (d, J = | oxazolidinone 250: methy|—3-(2- (CDCI3) 5 8.17 (dd, J = 5.9, 1.1 Hz, 1H), HRMS(B) ((S)(4- 7.47 — 7.23 (m, 8H), 7.18 — 7.05 (m, 3H), m/z phenoxyphenyl)ethy|amin 7.02 — 8.91 (m, 4H), 5.10 (br s, 1H), 4.22 467.2065 o)pyrimidinyl)—4- (s, 2H), 1.73 (s, 3H), 1.87 — 1.53 (m, 1H), (M + H) + phen onazolidinone 1.14 d, J = 7.0 Hz, 3H - 251: (S)(2-(1-(4- (CDCI3) 5 8.19 (d, J = 5.8 Hz, 1 H), 7.37 — HRMS(B) phenoxyphenyl)ethy|amin 7.28 (m, 5 H), 7.13 — 7.09 (m, 1 H), 7.01 — m/z midiny|)oxa 8.98 (m, 4 H), 5.47 (br s, 1 H), 5.12 — 5.05 431.2073 azaspiro[4.4]nonanone (m, 1 H), 4.11 — 4.07 (m, 2 H), 2.84 — 2.78 (M + H)+ (m, 1 H), 2.42 (brs, 1 H), 1.97— 1.88 (m, 1 H), 1.77 (br s, 1 H), 1.88 — 1.81 (m, 2 H), 1.58 (d, J = 8.9 Hz, 3 H), 1.54 — 1.48 (m, 2 252: (S)-4,4-dimethy|—3-(2- ) 5 8.19 (d, J = 5.8 Hz, 1H), 7.38 — MS m/z (1 -(4- 7.26 (m, 5H), 7.11 (tt, J = 74,11 Hz,1H), 405.1 (M phenoxyphenyl)ethy|amin 7.01 — 8.94 (m, 4H), 5.37 (br s, 1H), 5.01 + H) + o)pyrimidin (d, J = 9.1 Hz, 1H), 4.09 — 3.93 (m, 2H), y|)oxazo|idinone 1.71 (s, 3H), 1.57 (d, J = 8.9 Hz, 3H), 1.28 253: (S)(2-(((S)—1-(1- 8.49 (d, J = 5.7 Hz, 1H), 7.84 — 7.38 (m, HRMS(B) benzyImethyI-1H- 7H), 5.65 (s, 1.2H), 5.55 (s, 0.8H), 5.43 (M+H) pyrazoI (dq, J = 8.9, 8.9 Hz, 1H), 5.11 (tt, J = 8.1, 421.2338 y|)ethy|)amino)pyrimidin 3.8 Hz, 1H), 4.79 — 4.80 (m, 2H), 2.76 (dtt, y|)isopropy|oxazo|idin- J = 22.3, 7.2, 3.5 Hz, 1H), 2.56 (23, 3H), 2-one 1.87 (2d, J :89 Hz, 3H), 1.22 (2d, J = 7.1 , 1.13 dd, J = 8.9 Hz, 3H 254: (S)(2-(((S)—1-(1- 8.14 (d, J = 5.8 Hz, 1H), 7.50 (s, 1H), 7.38 HRMS(B) benzyImethyI-1H- (d, J = 5.8 Hz, 1H), 7.38 — 7.25 (m, 3H), (M+H) pyrazoI 7.24 — 7.17 (m, 2H), 5.21 (s, 2H), 5.06 (q, J 421.2340 y|)ethy|)amino)pyrimidin = 8.9 Hz, 1H), 4.78 (dt, J = 7.5, 3.9 Hz, isoprop onazolidin- 1H ,4.42—4.32 m, 2H , 2.38 brs, 1H 2.22 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H . 255: (4S)—4-isopropy|—3-(2- 1H NMR (400 MHz, MeOD) 5 8.16 (d, J = HRMS(B) (1-(1-methyI-1H-pyrazoI 5.8 Hz, 0.5H), 8.14 (d, J = 5.8 Hz, 0.5H), (M+H) y|)ethy|amino)pyrimidin 7.54 (s, 0.5H), 7.48 (s, 0.5H), 7.44 (s, 421.2340 y|)oxazolidinone 0.5H), 7.40 (d, J = 2.0 Hz, 0.5H), 7.38 (d, J = 2.0 Hz, 0.5H), 7.38 (s, 0.5H), 5.11 (q, J = 6.9 Hz, 1H), 4.75 (dq, J = 9.4, 3.7 Hz, 1H), 4.46 — 4.29 (m, 2H), 3.85 (d, J = 5.5 Hz, 3H), 2.62 (ddq, J = 10.4, 7.0, 3.5 Hz, 0.5H), 2.40 (br s, 0.5H), 1.53 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 7.1 Hz, 1.5H), 0.88 (d, J = 7.1 Hz, 1.5H), 0.86 (d, J = 7.0 Hz, 1.5H), 0.78 (d, J = 7.0 Hz, 1.5H).
HRMS(B) (M+H) 421.2340 Calc’d (M+H) 256: (S)(2-((S)—1-(3- 8.20 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 5.8 HRMS(B) (1 H-pyrazoI Hz, 1H), 7.75 (t, J = 2.0 Hz, 1H), 7.72 (d, J (M+H) y|)phenyl)ethylamino)pyri = 1.8 Hz, 1H), 7.58 (ddd, J = 8.0, 2.2, 1.0 393.2036 midiny|) Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.37 (d, J isopropyloxazolidinone = 5.8 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.56 — 6.49 (m, 1H), 5.13 (q, J = 7.0 Hz, 1H), 4.66 (br s, 1H), 4.39 — 4.19 (m, 2H), 1.82 (br s, 1H), 1.58 (d, J = 7.0 Hz, 3H), 0.56 br s, 6H . 257: (2-((S)—1-(4- 8.18 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 5.8 HRMS(B) (1 H-pyrazoI Hz, 1H), 7.72 (d, J :18 Hz, 1H), 7.69 (d, J (M+H) nyl)ethylamino)pyri = 1.9 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 393.2050 midiny|) 7.52 — 7.44 (m, 2H), 7.37 (d, J = 5.8 Hz, isopropyloxazolidinone 1H), 6.56 — 6.49 (m, 1H), 5.11 (q, J = 7.1 Hz, 1H), 4.68 (s, 1H), 4.40 — 4.24 (m, 2H), 1.86 (s, 1H), 1.57 (d, J = 7.1 Hz, 3H), 0.71 s, 3H , 0.59 s, 3H . 258: (4S)—4-isopropy|—3-(2- 8.17 (dd, J = 5.8, 4.6 Hz, 1H), 7.67 (s, HRMS(B) (1-(5-methyIphenyI-1H- 0.5H), 7.61 (s, 0.5H), 7.55 (dd, J = 8.5, 6.7 (M+H) pyrazoI Hz, 2H), 7.52 — 7.47 (m, 1H), 7.44 (ddd, J 407.2202 y|)ethy|amino)pyrimidin = 8.1, 3.3, 1.4 Hz, 2H), 7.40 (d, J = 5.8 Hz, y|)oxazolidinone 1H), 5.17 (dq, J =10.4,6.9 Hz, 1H), 4.83 — 4.77 (m, 1H), 4.45 — 4.34 (m, 2H), 2.66 (td, J = 7.0, 3.5 Hz, 0.5H), 2.45 (br s, 0.5H), 2.32 (s, 1.5H), 2.31 (s, 1.5H), 1.59 (dd, J = 6.8, 1.7 Hz, 3H), 1.01 (d, J = 7.0 Hz,1.5H), 0.94 — 0.85 (m, 3H), 0.81 (d, J = 6.9 Hz, 259: (R)—3-(2-((S)—1 - 8.80 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.10 HRMS(B) phenylethylamino)pyrimidi (d, J = 5.7 Hz, 1H), 7.89 (td, J = 7.7, 1.8 (M+H) nyl)—4-(pyridin Hz, 1H), 7.48 — 7.36 (m, 3H), 7.33 — 7.28 362.1617 y|)oxazolidinone (m, 4H), 7.21 (ddd, J = 8.8, 5.5, 2.2 Hz, 1H), 5.88 (br s, 1H), 4.79 (t, J = 8.9 Hz, 1H), 4.80 (br s, 1H), 4.31 (dd, J = 8.9, 3.8 1.22 , d, J = 6.6 Hz, 3H. 260: (S)(2-((S)—1-(2- 8.51 (d, J = 5.7 Hz, 1H), 7.78 — 7.51 (m, HRMS(B) fluoropheny|)ethy|amino)p 3H), 7.48 — 7.37 (m, 2H), 5.71 (q, J = 7.0 (M+H) Hz, 1H — 5.02 , 5.08 m, 1H ,4.75 — 4.81 393.2026 isopropyloxazolidinone (m, 2H), 2.30 (br s, 1H), 1.89 (d, J = 7.0, 3H), 1.10 (d, J = 7.1 Hz, 3H), 0.95 (d, J = 261: isopropy|—3-(2- 8.25 — 8.05 (m, 2H), 7.83 (dd, J = 8.6, 2.5 ) ((S)(6-phenoxypyridin- Hz, 1H), 7.50 — 7.34 (m, 3H), 7.27 — 7.16 (M+H) 3-y|)ethylamino)pyrimidin- (m, 1H), 7.15 — 7.02 (m, 2H), 6.89 (d, J = 420.2019 4-y|)oxazo|idinone 8.5 Hz, 1H), 5.10 (q, J = 7.1 Hz, 1H), 4.75 — 4.61 (m, 1H), 4.41 — 4.29 (m, 2H), 1.94 (br s, 1H), 1.56 (d, J = 7.1 Hz, 3H), 0.78 (br s, 3H , 0.70 br s, 3H . 262: (S)(5-f|uoro—2-(1 - 8.16 (d, J = 3.5 Hz, 1H), 7.45 — 7.28 (m, ) (4- 4H), 7.09 (tt, J = 7.3, 1.1 Hz, 1H), 7.02 — (M+H) phenoxyphenyl)ethy|amin 6.89 (m, 4H), 4.99 (q, J = 6.9 Hz, 1H), 4.58 395.1507 o)pyrimidin — 4.48 (m, 2H), 4.18 (ddd, J = 9.7, 8.5, 7.2 y|)oxazo|idinone Hz, 1H), 3.99 (br s, 1H), 1.52 (d, J = 6.9 263: (S)(2-(1-(4- 8.09 (d, J = 5.8 Hz, 1H), 7.43 — 7.29 (m, HRMS(B) phenoxyphenyl)ethy|amin 5H), 7.09 (tt, J = 7.3, 1.1 Hz, 1H), 7.00 — (M+H) midin 8.90 (m, 4H), 5.07 (q, J = 7.0 Hz, 1H), 4.53 377.1600 y|)oxazo|idinone — 4.41 (m, 2H), 4.21 (ddd, J = 10.5, 9.2, 7.0 Hz,1H),4.01 (brs, 1H), 1.53 (d, J = 264: (4S)—4-isopropy|—3-(2- 8.12 (dd, J = 8.5, 5.8 Hz, 1H), 7.35 (dd, J = ((1-(4-((tetrahydro—2H- 5.8, 1.0 Hz, 1H), 7.32 — 7.19 (m, 2H), 6.95 pyran — 6.86 (m, 2H), 4.98 (dq, J = 25.6, 7.2 Hz, y|)oxy)pheny|)ethy|)amino) 1H), 4.68 (br s, 0.5H), 4.59 — 4.48 (m, pyrimidiny|)oxazo|idin- 1.5H), 4.39 — 4.25 (m, 2H), 4.01 — 3.90 (m, 2-one 2H), 3.65 — 3.53 (m, 2H), 2.74 — 2.61 (m, 0.5H), 2.08 — 1.96 (m, 2H), 1.95 (br s, 0.5H), 1.78 — 1.64 (m, 2H), 1.50 (dd, J = 6.9, 1.6 Hz, 3H), 1.01 (d, J = 7.0 Hz,1.5H), 0.88 (d, J = 6.9 Hz, 1.5H), 0.75 (br s, 1.5H , 0.62 br s, 1.5H . 265: (S)(2-((S)—1-(4-(4- 8.14 (d, J = 5.8 Hz, 1H), 7.37 (d, J = 5.8 HRMS(B) fluorophenoxy)pheny|)eth Hz, 1H), 7.36 — 7.31 (m, 2H), 7.12 — 7.05 (M+H) ylamino)pyrimidiny|) (m, 2H), 7.01 — 6.94 (m, 2H), 6.94 — 6.89 437.1981 isopropyloxazolidinone (m, 2H), 5.06 (q, J = 7.0 Hz, 1H), 4.71 (br s, 1H), 4.41 — 4.29 (m, 2H), 1.99 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 0.77 (br s, 3H), 0.67 br s, 3H . 266: (R)—3-(2-((S)—1-(4- 8.46 (d, J = 5.8 Hz, 1H), 7.84 — 7.73 (m, HRMS(B) bromopheny|)ethy|amino) 5H), 7.72 — 7.67 (m, 1H), 7.64 (dd, J = 7.1, (M+H) pyrimidinyl)—4- 1.8 Hz, 2H), 7.59 — 7.53 (m, 2H), 5.92 (dd, 439.0762 phenyloxazolidin0ne J = 8.6, 4.0 Hz, 1H), 5.13 (t, J = 8.7 Hz, 1H), 4.98 (q, J = 8.4, 7.5 Hz, 1H), 4.55 (dd, J = 8.7, 4.0 Hz, 1H), 1.58 (d, J = 7.0 Hz, 3H . 267: (R)—3-(2-((S)—1 - 8.60 (d, J = 2.5 Hz, 1H), 8.55 (dd, J = 4.8, HRMS(B) phenylethylamino)pyrimidi 1.5 Hz, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.81 (M+H) ny|)(pyridin (dt, J = 7.8, 2.0 Hz, 1H), 7.54 — 7.47 (m, 362.1615 y|)oxazo|idinone 1H), 7.41 (d, J = 5.8 Hz, 1H), 7.36 — 7.25 (m, 4H), 7.25 — 7.17 (m, 1H), 5.60 (br s, 1H), 4.80 (t, J = 8.9 Hz, 1H), 4.61 (br s, 1H), 4.27 (dd, J = 9.0, 4.1 Hz, 1H), 1.25 (br d, J = 7.5 Hz, 3H. 268: (R)—3-(2-((S)-1 - 8.61 — 8.60 (m, 2H), 8.14 (d, J = 5.8 Hz, HRMS(B) phenylethylamino)pyrimidi 1H), 7.43 (d, J = 5.8 Hz, 1H), 7.42 — 7.37 (M+H) ny|)(pyridin (m, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.28 — 362.1610 y|)oxazo|idinone 7.17 (m, 3H), 5.57 (br s, 1H), 4.80 (t, J = 9.0 Hz, 1H), 4.55 (br s, 1H), 4.22 (dd, J = 9.0, 4.1 Hz, 1H , 1.20 br s, 3H. 269: (S)(2-((S)—1-(3- 8.46 (d, J = 5.7 Hz, 1H), 7.73 (d, J = 5.8 HRMS(B) methoxyphenyl)ethylamin Hz, 1H), 7.64 — 7.52 (m, 5H), 7.48 (t, J = (M+H) o)pyrimidinyl)—4- 7.8 Hz, 1H), 7.11 — 7.03 (m, 3H), 6.18 (dd, 391.1771 phenyloxazolidin0ne J = 8.7, 3.7 Hz, 1H), 5.25 — 5.13 (m, 2H), 4.60 (dd, J = 8.7, 3.7 Hz, 1H), 4.10 (s, 3H), 1.81 d, J = 7.0 Hz, 3H . 270: (4S)—3-(2-(1- 8.50 — 8.45 (m, 1H), 7.95 (ddt, J = 7.6, 5.3, HRMS(B) (biphenyI 2.3 Hz, 3H), 7.83 — 7.64 (m, 8H), 7.63 — (M+H) y|)ethylamino)pyrimidin 7.54 (m, 2H), 7.49 (dd, J = 4.9, 3.0 Hz, 84 y|)-5,5-dimethy|—4- 2H), 5.83 (s, 0.5H), 5.57 (s, 0.5H), 5.29 — phenyloxazolidin0ne 5.24 (m, 0.5H), 5.04 — 4.99 (m, 0.5H), 2.02 (s, 1.5H), 1.85 — 1.84 (m, 3H), 1.62 (d, J = 7.0 Hz,1.5H, 1.35 d, J = 3.3 Hz, 3H . 271: (S)(2-((S)(4- 8.15 (d, J = 5.8 Hz, 1H), 7.41 — 7.29 (m, HRMS(B) fluoropheny|)ethy|amino)p 2H), 7.25 (d, J = 5.8 Hz, 1H), 7.09 — 6.98 (M+H) yrimidiny|)isopropy|- (m, 2H), 4.96 (q, J = 7.1 Hz, 1H), 4.29 (d, J 359.1889 4-methyloxazolidinone = 9.0 Hz, 1H), 3.88 (d, J = 8.9 Hz, 1H), 2.17 (br s, 1H), 1.70 (s, 3H), 1.53 (d, J = 7.0 Hz, 3H), 0.70 (br s, 3H), 0.44 (br s, 3H . 272: (S)-4,4-dimethy|—3-(2- 8.12 (d, J = 5.8 Hz, 1H), 7.35 — 7.26i (m, HRMS(B) (1-(4-((4-methy|piperazin- 4H), 7.17 (d, J = 5.9 Hz, 1H), 5.02 (q, J = (M+H) 1- 6.9 Hz, 1H), 4.06 (q, J = 8.4 Hz, 2H), 3.51 425.2661 y|)methyl)phenyl)ethylami (s, 2H), 2.49 (br s, 8H), 2.28 (s, 3H), 1.70 no)pyrimidin (s, 3H), 1.53 (d, J = 7.0 Hz, 3H), 1.15 (br s, | idinone 3H . 273: 5-dimethy|—3- 8.09 (d, J = 5.8 Hz, 1H), 7.50 — 7.39 (m, HRMS(B) )(4-((4- 3H), 7.36 (tt, J = 7.1, 1.4 Hz, 1H), 7.30 (s, (M+H) methylpiperazin 4H), 7.21 (br s, 2H), 5.22 (br s, 1H), 4.58 501.2971 y|)methyl)phenyl)ethylami (br s, 1H), 3.53 (s, 2H), 2.50 (br s, 8H), no)pyrimidinyl)—4- 2.28 (s, 3H), 1.52 (s, 3H), 1.19 (d, J = 6.8 phen onazolidinone Hz, 3H , 0.99 s, 3H . 274: (S)-5,5-dimethy|—3-(2- 8.08 (d, J = 5.8 Hz, 1H), 7.45 (d, J = 5.8 HRMS(B) ((S)(4-((4- Hz, 1H), 7.38 — 7.23 (m, 3H), 7.16 (t, J = (M+H) methylpiperazin 7.5 Hz, 4H), 7.00 (br s, 2H), 5.51 (s, 1H), 501.2981 y|)methyl)phenyl)ethylami 4.89 — 4.83 (m, 1H), 3.49 (d, J = 2.3 Hz, no)pyrimidinyl)—4- 2H), 2.50 (br s, 8H), 2.29 (s, 3H), 1.67 (s, phen onazolidinone 3H 1.44 , d, J = 6.9 Hz, 3H , 1.00 s, 3H . 275: (S)isopropy|—4- 8.14 (d, J = 5.9 Hz, 1H), 7.29 (s, 4H), 7.24 methyl(2-((S)—1-(4-((4- (d, J = 5.9 Hz, 1H), 4.97 (p, J = 7.0 Hz, piperazin 1H), 4.60 (br s, 1H), 4.29 (d, J = 8.8 Hz, y|)methyl)phenyl)ethylami 1H), 3.88 (d, J = 9.0 Hz, 1H), 3.51 (s, 2H), no)pyrimidin 2.59 (br s, 8H), 2.28 (s, 3H), 1.71 (s, 3H), y|)oxazo|idinone 1.52 (d, J = 6.9 Hz, 3H), 0.70 (br s, 3H), 0.39 br s, 3H . 276: (S)isopropyI-5,5— 8.14 (d, J = 5.8 Hz,1H),7.39 — 7.20 (m, HRMS(B) dimethyl(2-(((S)—1-(4_ 5H), 5.09 (q, J = 7.0 Hz, 1H), 4.49 (br s, (M+H) ((4-methylpiperazin 1H), 3.52 (s, 2H), 2.57 (br s, 8H), 2.32 (s, 453.2975 3H ,2.03 br s, 1H no)pyrimidin = 7.0 Hz, 3H), 1.42 (s, 3H), 0.75 (br s, 3H), | oxazolidinone 0.62 br s, 3H . 277: (S)isopropy|—3-(2- 8.60 (ddd, J = 491.8, 1.0 Hz, 1H), 8.16 HRMS(B) ((S)(4-(pyridin (d, J = 5.8 Hz, 1H), 7.94 — 7.86 (m, 3H), (M+H) y|)phenyl)ethylamino)pyri 7.84 (dt, J = 7.9, 1.2 Hz, 1H), 7.51 — 7.43 404.2089 4-y|)oxazo|idin (m, 2H), 7.41 — 7.32 (m, 2H), 5.12 (q, J = one 7.0 Hz, 1H), 4.67 (br s, 1H), 4.40 — 4.18 (m, 2H), 1.83 (br s, 1H), 1.58 (d, J = 7.1 Hz, 3H , 0.68 br s, 3H , 0.56 br s, 3H . 278: (S)isopropy|—3-(2- 8.60 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 5.8 HRMS(B) -(6-pheny|pyridin Hz, 1H), 7.95 — 7.89 (m, 2H), 7.87 (dd, J = (M+H) y|)ethylamino)pyrimidin 8.2, 2.3 Hz, 1H), 7.81 (dd, J = 8.3, 0.8 Hz, 404.2079 y|)oxazo|idinone 1H), 7.55 — 7.42 (m, 3H), 7.40 (d, J = 5.8 Hz, 1H), 5.16 (q, J = 7.1 Hz, 1H), 4.66 (br s, 1H), 4.40 — 4.22 (m, 2H), 1.74 (br s, 1H), 1.62 (d, J = 7.0 Hz, 3H), 0.67 (br s, 3H), 0.57 br s, 3H . 279: (S)isopropy|—3-(2- 8.81 (dd, J = 4.3, 1.6 Hz, 1H), 8.32 (dt, J = HRMS(B) ((S)(quino|in 821.1 Hz, 1H), 8.18 (d, J = 5.8 Hz,1H), (M+H) y|)ethylamino)pyrimidin 8.01 (d, J = 8.7 Hz,1H),7.89 — 7.76 (m, 378.1930 y|)oxazo|idinone 2H), 7.53 (dd, J = 8.3, 4.4 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 5.24 (q, J = 7.1 Hz,1H), 4.59 (br s, 1H), 4.30 (t, J = 8.7 Hz, 1H), 4.22 (br s, 1H), 1.64 (d, J = 7.1 Hz, 3H), 1.49 brs, 1H ,0.35 brs, 6H. 280: (S)isopropy|—3-(2- 8.81 (dd, J = 4.3, 1.7 Hz, 1H), 8.34 (dt, J = HRMS(B) ((S)(quino|in 8412 Hz, 1H), 8.13 (d, J = 5.9 Hz,1H), (M+H) y|)ethylamino)pyrimidin 8.00 (d, J :16 Hz, 1H), 7.93 (d, J = 8.5 378.1941 y|)oxazo|idinone Hz, 1H), 7.68 (dd, J = 8.6, 1.8 Hz, 1H), 7.50 (dd, J = 8.3, 4.4 Hz, 1H), 7.36 (d, J = .8 Hz, 1H), 5.23 — 5.17 (m, 1H), 4.50 (br d, J = 84.2 Hz, 1H), 4.35 — 4.25 (m, 1H), 4.19 (br s, 1H), 2.68 (pd, J = 7.0, 3.5 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H , 0.86 d, J = 6.9 Hz, 3H. 281: (S)(2-((S)(4- 8.17 (d, J = 5.8 Hz,1H),7.81— 7.71 (m, HRMS(B) lphenyl)ethylamino 4H), 7.69 — 7.61 (m, 1H), 7.59 — 7.49 (m, (M+H) idinyl)—4- 4H), 7.39 (d, J = 5.8 Hz, 1H), 5.15 (q, J = 431.2072 isopropyloxazolidinone 7.1 Hz,1H),4.67(br s, 1H), 4.41 — 4.23 (m, 2H), 1.75 (br s, 1H), 1.58 (d, J = 7.1 Hz, 3H , 0.69 br s, 3H , 0.61 br s, 3H . 282 : (S)(2-((S)—1-(3- 8.18 (d, J = 7.1 Hz, 1H), 7.75 (d, J = 7.3 HRMS(B) fluoro—4-(2-methyI-1H- Hz, 1H), 7.71 — 7.62 (m, 3H), 7.58 (dd, J = (M+H) imidazoI 10.9, 1.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.8 Hz, 425.2093 y|)phenyl)ethylamino)pyri 1H), 5.33 (br s, 1H), 4.81 — 4.73 (m, 1H), midiny|) 4.46 — 4.36 (m, 2H), 2.54 (s, 3H), 2.03 (br isopropyloxazolidinone s, 1H), 1.64 (d, J = 7.0 Hz, 3H), 0.84 (br d, J = 7.2 Hz, 3H , 0.70 br d, J = 7.2 Hz, 3H . 283: (4S)—4-isopropy|—3-(2- 8.15 (dd, J = 8.9, 5.8 Hz, 1H), 7.60 — 7.50 HRMS(B) (1-(4-(2-methyI-1H- (m, 2H), 7.42 — 7.32 (m, 3H), 7.14 (dd, J = (M+) imidazoI 13.3, 1.5 Hz, 1H), 6.96 (dd, J = 3.5, 1.5 Hz, 406.2217 nyl)ethylamino)pyri 1H), 5.17 (q, J = 7.1 Hz, 0.5H), 5.07 (d, J = midiny|)oxazo|idin 7.4 Hz, 0.5H), 4.71 (br s, 0.5H), 4.50 (br s, one 0.5H), 4.40 — 4.24 (m, 2H), 2.67 (ddq, J = .6, 7.0, 3.6 Hz, 0.5H , 2.323 s, 1.5H 2.321 (s, 1.5H), 1.95 (br s, 0.5H), 1.58 (dd, J = 7.0, 2.3 Hz, 3H), 1.02 (d, J = 7.0 Hz, 1.5H), 0.88 (d, J = 6.9 Hz, 1.5H), 0.76 (br s,1.5H,0.64 brs,1.5H . 284: (S)(2-(((R)—1- HRMS(B) cyclopentylethyl)amino)py m/z rimidiny|) 319.2133 isopropyloxazolidinone (M+H )+, RT=2.68 min. 285: (S)(2-(((S)—1-(4- HRMS(B) hylamino)phenyl)et m/z hyl)amino)pyrimidiny|)- 370.2227 4-isopropyloxazolidin (M+H )+, one RT=2.47 min. 286: N-(3-((S)—1-((4-((S)— HRMS(B) 4-isopropyI m/z oxooxazolidin 384.2032 y|)pyrimidiny|)amino) (M+H )+, Ethylphenyl)acetamide RT=1.97 287: (S)(2-(((S)—1-(1H- HRMS(B) benzo[d]imidazoI m/z y|)ethy|)amino)pyrimidin 367.1887 y|)isopropy|oxazo|idin- (M+H )+ 2-one RT=2.39 288: (S)(2-(((S)—1-(4- HRMS(B) ((4- m/z pheny|)su|fony|)phe 501.1343, ny|)ethy|)amino)pyrimidin- (M+H )+ 4-y|) RT=2.68 isoprop onazolidinone min. 289: (S)isopropy|—3-(2- HRMS(B) (((S)(4- m/z nitrophenyl)ethy|)amino)p 372.1672, yrimidinyl)oxazolidin (M+H )+, one 9 min. 290: (S)(2-(((S)—1-(4- HRMS(B) aminophenyl)ethy|)amino) m/z pyrimidinyl)—4- 342.1931, isopropyloxazolidinone (M+H )+, RT=2.17 291: (S)isopropy|—3-(2- HRMS(B) (((S)—1-(5-(methy|thio)— m/z 1,3,4-oxadiazol 365.1367, y|)ethy|)amino) (M+H )+, dinyl)oxazolidin- RT=1.88 2-one min. 292: isopropy|—3-(2- (CDCI3) 5 8.15 (d, J = 5.9 Hz, 1H), 7.87 — HRMS(B) 1-(5-phenyI-1,3,4- 7.74 (m, 2H), 7.51 (d, J = 5.9 Hz, 1H), 7.46 m/z thiadiazoI leth | . . . 411.1596 2012/055133 amino) din 4.58 (dt, J = 8.3, 3.3 Hz, 1H), 4.29 — 4.12 M +H)+, y|)oxazo|idinone (m,2H), 1.94 — 1.80 (b, 1H), 1.74 (d, J = RT=2.54m 7.0 Hz, 3H), 0.69 (d, J = 6.8 HZ, 3H), 0.60 in. d, J = 7.2 Hz, 3H 293: (S){2-[1-(5-Ch|oro— HRMS(B) 1H-benzoimidazolyl)— m/z ethylamino]—pyrimidin 14, y|}isopropy|—oxazo|idin- RT=2.04 2-one min. 294: (S)(2-{(S)—1-[5- (CDCI3) 5 8.22 (d, J = 5.7 Hz, 1.0 H), 7.52 HRMS(B) (2,2-Dimethyl-propyl)— (d, J = 5.8 Hz, 0.95 H), 5.92 (s, 0.96 H), m/z isoxazoIyI]-ethy|amino}- 5.50 (d, J = 7.5 Hz, 0.97 H), 5.22 (s, 387.2271 pyrimidinyl)—4- 0.83H), 4.72 (d, J = 8.3 Hz, 1.0 H), 4.42 — isopropyI-oxazolidinone 4.20 (m, 2.06 H), 3.51 (s, 0.27 H), 2.61 (s, 2.05 H), 1.62 (d, J = 7.0 Hz, 4.13 H), 0.97 (s, 8.95 H), 0.90 (d, J = 7.0 Hz, 2.56 H), 0.80 d, J = 7.0 Hz, 2.93 H . 295: (4S)—4-isopropy|—3-(2- (CDCI3) 5 8.93 (d, J = 5.9 Hz, 4H), 8.26 — HRMS(B) (1 -(5-pheny|pyrimidin 8.17 (m, 2H), 7.84 — 7.44 (m, 12H), 8.41 m/z y|)ethylamino)pyrimidin (br s, 1H), 5.31 (br s, 1H), 4.79 — 4.85 (m, 405.2024 y|)oxazo|idinone 2H), 4.41 — 4.24 (m, 4H), 2.65 (dddd, J = and 27.4, 14.1, 7.1, 3.5 Hz, 1H), 2.20 (br s, 405.2025 1H), 1.75-1.84 (m, 4H), 1.07 — 0.85 (m, (M + H)+. 296: 4-{(S)[4-((S)—4- HRMS(B) IsopropyIoxo- (W) = oxazolidinyl)—pyrimidin- 467.2533 2-y|amino]—ethy|}- RT.: 2.83 piperidine—1-carboxylic min. acid benz | ester 297: (S)(2-((S)—1-(5- HRMS(B) bromopyridin m/z y|)ethylamino)pyrimidin 406.0870 y|)isopropy|oxazo|idin- (M + H)+. 2-one. RT.: 2.50 min. 298: 3-(5-fluoro—2-((1-(5- HRMS(B) (4-fluoro m/z methylphenyl)pyridin 412.1578 y|)ethy|)amino)pyrimidin (M + H)+. y|)oxazo|idinone RT.: 2.35 min. 299: 3-(2-(1-(5-(4- HRMS(B) fluorophenoxy)pyrimidin- m/z thy|amino)pyrimidin- 411.1572 4-y|)oxazo|idinone. (M + H)+.
RT.: 2.25 min. 300: 3-(5-fluoro—2-(1-(5-(4- ) fluorophenoxy)pyrimidin- m/z thy|amino)pyrimidin- 415.1320 4-y|)oxazo|idinone. (M + H)+.
RT.: 2.26 min. 301: 48 2- 1- 5- 2,4- CDCI3 6 8.45 d, J = 4.6 Hz, 4H , 8.21 d, difluorobenzyloxy)pyrimidi J = 5.8 Hz, 2H), 7.53 — 7.41 (m, 4H), 6.93 471.8 (M n (ddddd, J = 19.9, 9.8, 8.7, 2.6, 1.2 Hz, 4H), + H)+_ y|)ethy|amino)pyrimidin 6.21 (s, 1H), 6.11 (s, 1H), 5.21 (brs, 2H), y|)isopropy|oxazo|idin- 5.18 (s, 2H), 5.16 (s, 2H), 4.74 (dt, J = 7.7, 2-one 3.3 Hz, 1H), 4.66 (d, J = 7.4 Hz, 1H), 4.38 — 4.24 (m, 4H), 2.65 (ddq, J = 10.5, 7.1, 3.5 Hz, 1H), 2.30 (br s, 1H), 1.65-1.59 (m, 6H),1.01 (d, J = 7.0 Hz, 3H), 0.89 (dq, J = 7.6, 4.9, 4.4 Hz, 6H), 0.79 (d, J = 6.5 Hz, 302: (S)(2-{(S)[4-(4- LC-MS —phenoxy)— m/z cyclohexyl]—ethy|amino}- 442.53 (M pyrimidiny|) + H)+; isopropyI-oxazolidinone RT.: 1.77 min. 303: (4S)—3-(2-(1-(5-(5- (CDCI3) 6 8.62 — 8.49 (m, 6H), 8.44 — 8.36 HRMS(B) bromopyridin-3— (m, 2H), 8.22 (dd, J = 5.7, 0.6 Hz, 2H), m/z y|oxy)pyrimidin 7.57 — 7.46 (m, 4H), 6.14 (br s, 2H), 5.33 500.1038 y|)ethy|amino)pyrimidin (br s, 2H), 4.76 (dt, J = 8.2, 3.4 Hz, 1H), and y|)isopropy|oxazo|idin- 4.67 (s, 1H), 4.40 — 4.26 (m, 4H), 2.67 (pd, 500.1034 2-one J = 7.0, 3.4 Hz, 1H), 2.32 (br s, 1H), 1.69 — (M + H)+. 1.61 (m, 6H), 1.02 (d, J = 7.0 Hz, 3H), 0.99 —0.80 m, 9H . 304: (S)(2-((S)—1-(5- ) 6 8.58 (s, 2H), 8.12 (d, J = 5.8 Hz, LC-MS chloropyrimidin 1H), 7.40 (d, J = 5.8 Hz, 1H), 5.97 (br s, m/z 363.1 y|)ethy|amino)pyrimidin 1H), 5.17 (br s, 1H), 4.63 (dt, J = 8.0, 3.2 (M + H)+; isopropy|oxazo|idin- Hz, 1H), 4.29 — 4.15 (m, 2H), 2.10 (br s, RT.: 1.39 2-one. 1H), 1.50 — 1.46 (m, 3H), 0.88 — 0.66 (m, min. 6H . 305: (S)(2-((S)—1-(5-(3- (CDCI3) 6 8.36 (s, 2H), 8.13 (s, 1H), 7.41 HRMS(B) chloro—4- (d, J = 5.4 Hz, 1H), 7.15 — 7.00 (m, 2H), m/z fluorophenoxy)pyrimidin- 6.85 (ddd, J = 9.0, 3.7, 3.0 Hz, 1H), 6.08 473.1484 2-y|)ethy|amino)pyrimidin- (s, 1H), 5.21 (br s, 1H), 4.66 (dt, J = 8.3, (M + H)+. 4-y|) 3.4 Hz, 1H), 4.30 — 4.16 (m, 2H), 2.25 (br isopropyloxazolidinone. s, 1H), 1.56-1.51 (m, 3H), 0.85-0.78 (m, 3H — 0.70 , 0.77 m, 3H . 306: (4S)—4-isopropy|—3-(2- HRMS(B) (1 -(5-(pyridin m/z y|oxy)pyrimidin 422.1938, y|amino)pyrimidin RT y|)oxazolidinone 1.91min 422.1944, 2.01min M + H +. 307: -(2-(1-(5-(3- (CDCI3) 6 8.43 (d, J = 4.9 Hz, 4H), 8.21 (d, HRMS(B) fluorobenzyloxy)pyrimidin- J = 5.7 Hz, 2H), 7.49 — 7.34 (m, 4H), 7.26 m/z 2-y|)ethy|amino)pyrimidin- — 7.02 (m, 6H), 6.20 ( br s, 1H), 6.11 (br s, 453.2048 4-y|) 1H), 5.22 (br s, 2H), 5.16 (s, 2H), 4.74 (dt, and isopropyloxazolidinone J = 7.7, 3.3 Hz, 1H), 4.66 (br s, 1H), 4.38 — 453.2047 4.23 (m, 4H), 2.66 (heptd, J = 7.0, 3.5 Hz, (M + H)+. 1H), 2.26 (br s, 1H), 1.64-1.58 (m, 6H), 1.00 d, J = 7.0 Hz, 3H — 0.85 , 0.94 m, —--—— 308: (S)(2-((S)—1-(5- HRMS(B) iodopyrimidin m/z y|)ethy|amino)pyrimidin 454.0614 yl)isopropyloxazolidin- (M +). RT 2-one. 2.35min 309: (4S)—4-isopropyl(2- HRMS(B) (1-(5-(5- m/z (trifluoromethyl)pyridin 490.1800, y|oxy)pyrimidin RT y|)ethy|amino)pyrimidin 2.17min y|)oxazolidinone and 490.1795, M + H + 310: (4S)—4-isopropyl(2- HRMS(B) (1-(pyrimidin m/z yl)ethylamino)pyrimidin 329.1728, y|)oxazolidinone RT 1.81min 329.1726, M + H +. 311: (4S)—3-(2-(1-(4-(4- (CDCI3) 5 8.56 (dd, J = 5.7, 2.3 Hz, 2H), HRMS(B) fluorophenoxy)pyrimidin- 8.20 (dd, J = 5.7, 4.0 Hz, 2H), 7.46 (dd, J = m/z 2-yl)ethylamino)pyrimidin- 5.7, 4.4 Hz, 2H), 7.20 — 7.00 (m, 8H), 6.71 439.1887 4-yl) (dd, J = 5.7, 2.0 Hz, 2H), 6.03 (br s, 1H), and isopropyloxazolidinone 5.87 (br s, 1H), 5.11 (br s, 2H), 4.72 — 4.61 439.1887 (m, 2H), 4.40 — 4.23 (m, 4H), 2.59 (ddp, J (M + H)+. = 10.5, 7.1, 3.5 Hz, 1H), 2.21 (brs,1H), 1.59-1.55 (m, 6H), 1.00 — 0.85 (m, 9H), 0.80 d, J = 6.3 Hz, 3H. 312: (2-((S)(4- H NMR (400 MHz, CD30D) 5 ppm 0.63 LCMS m/z (((2S,6R)—2,6- (br. s., 3 H) 0.79 (br. s., 3 H) 1.20 (dd, 454.3 dimethylmorpholino)methy , 2.74 Hz, 6 H) 1.58 (d, J=7.04 Hz, 3 (M + H)+, l)phenyl)ethylamino)pyrimi H) 2.54 - 2.82 (m, 2H) 3.73 - 3.90 (m, 2 H) Rt 0.57 dinyl) 4.32 (d, J=3.52 Hz, 2 H) 4.39 (d, J=5.87 min isopropyloxazolidinone Hz, 2 H) 4.68 - 4.78 (m, 1 H) 5.15 - 5.31 (m, 1 H) 7.51 (s, 4 H) 7.62 - 7.76 (m, 1 H) 8.08 - 8.22 (m, 1 H) The compounds in Table 9 were prepared using methods substantially similar to those described for the ation of Examples 1, 113, and 171 through 212, ing chiral separation to isolate the two diastereomers.
Table 9. 313&314 6 317&318 337 & 338 339 & 340 341 & 342 WO 46136 343 & 344 349 & 350 361 & 362 367 & 368 369 & 370 371 & 372 WO 46136 375 & 376 403 & 404 405 & 406 407 & 408 8 419&420 428 & 429 431 & 432 433 & 434 435 & 436 WO 46136 437 & 438 439 & 440 441 & 442 448 & 449 454 & 455 Table 10. Chemical name, NMR chemical shifts, chiral separation ions and LCMS signal for each compound listed in Table 9.
Example: Name Chiral separation conditions, peak identification and anal tical data 331 & 314: 4-(4- The chiral separation was carried outwith SFC (IA-H, methoxyphenyl)-5,5- 5pM, 20 x 50 mm) using 28% MeOH in CO2 to give (R)- dimethyl(2-((S)—1-(4- 4-(4-methoxyphenyl)-5,5-dimethyl(2-(((S)—1-(4- phenoxyphenyl)ethylamin phenoxyphenyl)ethyl)amino)pyrimidinyl)oxazolidin midin one and (S)(4-methoxyphenyl)-5,5-dimethyl(2- yl)oxazolidinone (((S)(4-phenoxyphenyl)ethyl)amino)pyrimidin yl)oxazolidinone. 1St Peak 313: 1H NMR (400 MHz, CDCI3) 6 8.03 (dd, J = .9, 1.6 Hz, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.30 — 7.22 (m, 2H), 7.20 — 7.14 (m, 2H), 7.06 — 7.00 (m, 1H), 6.98 (d, J = 8.2 Hz, 2H), 6.94 — 6.86 (m, 4H), 6.83 — 6.76 (m, 2H), 5.24 (br s, 1H), 5.01 (s, 1H), 4.57 (br s, 1H), 3.72 (s, 3H), 1.46 (s, 3H), 1.24 — 1.09 (m, 3H), 0.92 (s, 3H); HRMS(B) m/z 511.2326 (M + H) +. 2nd Peak 314 : 1H NMR (400 MHz, 00013) 5 8.11 (d, J = .7 Hz, 1H), 7.51 (d, J = 5.7 Hz, 1H), 7.38 — 7.29 (m, 2H), 7.10 (tt, J = 7.3, 1.2 Hz, 1H), 7.06 — 6.90 (m, 6H), 6.89 — 6.82 (m, 2H), 6.82 — 6.75 (m, 2H), 5.29 (s, 1H), .09 (br s, 1H), 4.80 (br s, 1H), 3.72 (s, 3H), 1.63 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.01 (s, 3H); HRMS(B) m/z 511.2323 M + H +. 315 & 316: methyl- The chiral separation was carried out with SFC (IA, 4-phenyl(2-(1-(1- 5pm, 20 x 250 mm) using 45% iPrOH with 0.2% Et2NH phenyl-1H-pyrazol in CO2 to give (S)methylphenyl(2-(((R)(1- y|)ethy|amino)pyrimidin phenyl-1H-pyrazolyl)ethyl)amino)pyrimidin y|)oxazolidinone y|)oxazolidinone and (S)methylphenyl(2- (((S)(1-phenyl-1H-pyrazolyl)ethyl)amino)pyrimidin- 4-yl)oxazolidinone. 1st Peak 315: 1H NMR (400 MHz, CDCI3) 5 8.19 (d, J = .8 Hz, 1 H), 7.63 — 7.60 (m, 2 H), 7.49 — 7.44 (m, 4 H), 7.37 — 7.28 (m, 4 H), 7.26 — 7.22 (m, 2 H), 7.12 — 7.08 (m, 1 H), 4.94 (br s, 1 H), 4.45 (br s, 1 H), 4.31 — 4.27 (m, 2 H), 2.19 (s, 3 H), 1.44 (d, J = 6.8 Hz, 3 H); HRMS(B) m/z 441.2036 (M + H)+. 2nd Peak 316:1H NMR (400 MHz, CDCI3) 5 8.20 (d, J = .8 Hz, 1 H), 7.67 — 7.63 (m, 3 H), 7.53 (s, 1 H), 7.49 — 7.44 (m, 3 H), 7.40 — 7.37 (m, 2 H), 7.33 — 7.30 (m, 4 H), 4.99 (br s, 1 H), 4.38 (br s, 1 H), 4.26 (s, 2 H), 2.00 (s, 3 H), 1.07 (br s, 3 H); HRMS(B) m/z 39 (M + 317 & 318: (R)—4-methy|— The chiral separation was carried out with SFC (IA, yl(2-(1-(1- 5pm, 20 x 250 mm) with 45% iPrOH modified with 0.2% phenyl-1H-pyrazol Et2NH in CO2 to give (R)—4-methylphenyl(2-(((S)- y|)ethy|amino)pyrimidin 1-(1-phenyl-1H-pyrazolyl)ethyl)amino)pyrimidin y|)oxazolidinone y|)oxazolidinone and (S)methylphenyl(2- (((S)(1-phenyl-1H-pyrazolyl)ethyl)amino)pyrimidin- xazolidinone. 1st peak 317:1H NMR (400 MHz, CDCI3) 5 8.20 (d, J = .8 Hz, 1 H), 7.68 — 7.63 (m, 3 H), 7.53 (s, 1 H), 7.49 — 7.44 (m, 3 H), 7.41 — 7.37 (m, 2 H), 7.33 — 7.30 (m, 4 H), 4.98 (br s, 1 H), 4.39 (br s, 1 H), 4.26 (s, 2 H), 2.00 (s, 3 H), 1.07 (br s, 3 H); HRMS(B) m/z 441.2037 (M + H)+. 2nd peak 318:1H NMR (400 MHz, CDCI3) 5 8.17 (d, J = .8 Hz, 1 H), 7.63 — 7.60 (m, 2 H), 7.49 — 7.44 (m, 4 H), 7.36 — 7.29 (m, 4 H), 7.26 — 7.22 (m, 2 H), 7.12 — 7.08 (m, 1 H), 5.02 (br s, 1 H), 4.45 (br s, 1 H), 4.31 — 4.26 (m, 2 H), 2.19 (s, 3 H), 1.44 (d, J = 6.8 Hz, 3 H); HRMS B m/z 441.2039 M + H +. 319 & 320: (R)—4-(4- Separation was achieved on a normal phase silica gel fluorophenyl)—3-(2-(1-(1- column with 10 to 50% ethylacetate/ heptane to give (4-fluorophenyl)-1H- (R)—4-(4-fluorophenyl)—3-(2-(((R)—1-(1-(4-fluorophenyl)- pyrazoI 1H-pyrazolyl)ethyl)amino)pyrimidinyl)—4- y|)ethy|amino)pyrimidin methyloxazolidinone and (R)—4-(4-fluorophenyl)—3-(2- y|)methyloxazolidin (((S)(1-(4-fluorophenyl)-1H-pyrazol one yl)ethyl)amino)pyrimidinyl)methyloxazolidinone. 1st peak 319:1H NMR (400 MHz, CDCI3) 5 8.10 (d, J = .8 Hz, 1 H), 7.53 — 7.48 (m, 3 H), 7.44 (s, 1 H), 7.36 (d, J = 5.8 Hz, 1 H), 7.22 — 7.17 (m, 2 H), 7.09 — 7.03 (m, 2 H), 7.01 — 6.95 (m, 2 H), 4.98 (br s, 1 H), 4.33 (br s, 1 H), 4.15 (q, J = 8.6 Hz, 2 H), 1.90 (s, 3 H), 1.04 (br s, 3 H); HRMS(B) m/z 477.1827 (M + H)+. 2nd peak 320: 1H NMR (400 MHz, CDCI3) 5 8.18 (d, J = .8 Hz, 1 H), 7.62 — 7.56 (m, 2 H), 7.45 — 7.39 (m, 3 H), 7.31 — 7.26 (m, 2 H), 7.18 — 7.12 (m, 2 H), 6.93 (t, J = 8.6 Hz, 2 H ,5.01 brs, 1 H brs, 1 H , 4.50 , 4.30— 4.23 (m, 2 H), 2.17 (s, 3 H), 1.45 (d, J = 6.8 Hz, 3 H); HRMS B m/z 29 M + H +. 321 & 322: (S) Separation was achieved on a normal phase silica gel pyl(2-(1-(1-(3- column with 10 to 50% ethylacetate/ heptane to give methoxyphenyl)—1H- isopropyl(2-(((R)—1-(1-(3-methoxyphenyl)—1 H- pyrazol pyrazolyl)ethyl)amino)pyrimidinyl)oxazolidinone y|)ethy|amino)pyrimidin and (S)isopropyl(2-(((S)—1-(1-(3-methoxyphenyl)— y|)oxazolidinone 1H-pyrazolyl)ethyl)amino)pyrimidinyl)oxazolidin one. 1st peak 321:1H NMR (400 MHz, MeOD) 6 8.18 (dd, J = 3.3, 2.5 Hz, 2H), 7.70 (s, 1H), 7.42 (d, J = 5.8 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.31 (t, J = 2.3 Hz, 1H), 7.27 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 6.89 (ddd, J = 8.1, 2.5, 0.9 Hz, 1H), 5.21 (q, J = 6.8 Hz, 1H), 4.81 — 4.73 (m, 1H), 4.44 — 4.34 (m, 2H), 3.87 (s, 3H), 2.64 (pd, J = 7.0, 3.5 Hz, 1H), 1.61 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H).HRMS(B) (M+H) 41 Calc’d (M+H) 423.2145 2nd peak 322: 1H NMR (400 MHz, MeOD) 6 8.18 (d, J = .8 Hz, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.41 (d, J = 5.8 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.28 (t, J = 2.3 Hz, 1H), 7.24 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 6.88 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 5.19 (q, J = 6.9 Hz, 1H), 4.74 (dt, J = 7.6, 3.5 Hz, 1H), 4.42 — 4.28 (m, 2H), 3.86 (s, 3H), 2.31 (br s,1H),1.61 (d, J = 6.9 Hz, 3H), 0.79 (br s, 3H), 0.75 — 0.64 (br m, 3H). ) (M+H) 423.2139 Calc’d M+H 423.2145 323 & 324: 4-(4-(1-(4-((S)— Chiral separation was achieved by SFC. (Column: 4-isopropyl Chiralpak-ID (Semi-Prep 20mm x 250mm) oxooxazolidin lsocratic:65%CO2:35%MeOH (5mM NH4OH ve) y|)pyrimidin to give (S)isopropyl(2-(((R)—1-(1-(3- ylamino)ethyl)methyl- methoxyphenyl)—1H-pyrazolyl)ethyl)amino)pyrimidin- 1 H-pyrazol 4-yl)oxazolidinone and (S)isopropyl(2-(((S) y|)benzonitrile (1-(3-methoxyphenyl)—1H-pyrazol yl)ethyl)amino)pyrimidinyl)oxazolidinone. 1st peak 323:1H NMR (400 MHz, MeOD) 6 8.16 (d, J = .8 Hz, 1H), 7.95 — 7.88 (m, 2H), 7.75 (s, 1H), 7.73 — 7.67 (m, 2H), 7.40 (d, J = 5.8 Hz, 1H), 5.19 (q, J = 6.9 Hz, 1H), 4.79 (td, J = 5.7, 3.5 Hz, 1H), 4.40 (d, J = 5.7 Hz, 2H), 2.65 (pd, J = 7.0, 3.6 Hz, 1H), 2.41 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 432.2138 Calc’d (M+H) 432.2148 2nd peak 324: 1H NMR (400 MHz, MeOD) 5 8.17 (d, J = .8 Hz, 1H), 7.97 — 7.84 (m, 2H), 7.77 — 7.63 (m, 3H), 7.40 (d, J = 5.8 Hz, 1H), 5.16 (q, J = 6.8 Hz,1H),4.79 (dt, J = 7.5, 3.8 Hz, 1H), 4.43 — 4.33 (m, 2H), 2.41 (s, 4H), 1.59 (d, J = 6.9 Hz, 3H), 0.87 (br d, J = 7.1 Hz, 3H), 0.80 (br d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 432.2137 Calc’d M+H 432.2148 325 & 326: (S)(2-(1- Chiral separation was achieved by chiral SFC column (3,5-dimethylphenyl- chromatography (Column AD-H 5mM 20x250mm 1 H-pyrazol column 15% MeOH+DEA) to give (S)—3-(2-(((R)—1-(3,5- y|)ethy|amino)pyrimidin dimethylphenyl-1H-pyrazol is000ro loxazolidin- leth lamino o rimidin lis000ro loxazolidin one and (S)—3-(2-(((S)—1-(3,5-dimethylphenyl-1 H- pyrazolyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone. 1st peak 325: 1H NMR (400 MHz, MeOD) 6 8.16 (d, J = .8 Hz, 1H), 7.57 — 7.49 (m, 2H), 7.48 — 7.42 (m, 1H), 7.42 — 7.38 (m, 3H), 5.12 (q, J = 7.0 Hz, 1H), 4.78 (td, J = 5.6, 3.5 Hz, 1H), 4.44 — 4.36 (m, 2H), 2.63 (td, J = 7.0, 3.6 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 421.2348 Calc’d (M+H) 421.2352 2nd peak 326: 1H NMR (400 MHz, MeOD) 6 8.18 (d, J = .8 Hz, 1H), 7.56 — 7.49 (m, 2H), 7.48 — 7.41 (m, 1H), 7.40 — 7.35 (m, 3H), 5.07 (q, J = 7.1 Hz, 1H), 4.78 (dt, J = 7.8, 3.8 Hz, 1H), 4.44 — 4.32 (m, 2H), 2.33 (s, 3H), 2.31 (br s, 1H) 2.29 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H), 0.85 (br d, J = 7.0 Hz, 3H), 0.77 (br d, J = 6.9 Hz, 3H).
HRMS B M+H 421.2347 Calc’d M+H 421.2352 327 & 328: (S)(2-(1-(4- Separation was achieved by reverse HPLC % (1 H-imidazol ACN/water 0.1% NH4OH modifier) to give (S)(2- yl)phenyl)ethylamino)pyri (((R)—1-(4-(1 H-imidazol midiny|) yl)phenyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone isopropyloxazolidinone and (S)(2-(((S)(4-(1H- imidazoly|)phenyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone. 1st peak 327: 1H NMR (400 MHz, MeOD) 6 8.25 — 8.00 (m, 2H), 7.53 (d, J = 0.7 Hz, 5H), 7.38 (d, J = 5.9 Hz, 1H), 7.15 (s, 1H), 5.04 (q, J = 7.1 Hz, 1H), 4.50 (br s, 1H), 4.40 — 4.19 (m, 2H), 2.68 (pd, J = 7.0, 3.6 Hz,1H), 1.57 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 42 Calc’d (M+H) 393.2039 2nd peak 328:1H NMR (400 MHz, MeOD) 6 8.16 (d, J = .8 Hz, 1H), 8.10 (t, J = 1.2 Hz, 1H), 7.55 (t, J = 1.4 Hz, 1H), 7.52 (s, 4H), 7.38 (d, J = 5.8 Hz, 1H), 7.15 (t, J = 1.2 Hz, 1H), 5.12 (q, J = 7.0 Hz, 1H), 4.67 (br s,1H), 4.44 — 4.23 (m, 2H), 1.84 (br s, 1H), 1.57 (d, J = 7.0 Hz, 3H), 0.71 (br s, 3H), 0.60 (br s, 3H). HRMS(B) (M+H) 393.2026 Calc’d M+H 393.2039 329 & 330: (S)(2-(1-(3- Chiral separation was ed by chiral SFC column fluoro(pyridin chromatography (Column AD-H 5mM 20x250mm yloxy)phenyl)ethylamino)p column 15% MeOH+DEA) to give (S)—3-(2-(((R)—1-(3- yrimidinyl)—4- fluoro(pyridinyloxy)phenyl)ethyl)amino)pyrimidin isopropyloxazolidinone yl)isopropy|oxazolidinone and (S)—3-(2-(((S)—1-(3- fluoro(pyridinyloxy)phenyl)ethyl)amino)pyrimidin isopropyloxazolidinone. 1st peak 329: 1H NMR (400 MHz, MeOD) 6 8.32 — 8.23 (m, 2H), 8.15 (d, J = 5.8 Hz, 1H), 7.45 — 7.35 (m, 3H), 7.31 (dd, J = 11.8, 2.0 Hz, 1H), 7.26 (dd, J = 8.5, 2.0 Hz, 1H), 7.19 (t, J = 8.2 Hz, 1H), 5.15 — 4.95 (m, 1H), 4.51 (s, 1H), 4.41 — 4.26 (m, 2H), 2.68 (pd, J = 7.1, 3.6 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). ) (M+H) 438.1935 Calc’d (M+H) 438.1941 2nd peak 330: 1H NMR (400 MHz, MeOD) 6 8.28 (dd, J = 47,14 Hz, 1H , 8.26 d, J :28 Hz, 1H , 8.17 d, J = WO 46136 21 1 .8 Hz, 1H), 7.43 — 7.40 (m, 2H), 7.36 (ddd, J = 8.4, 2.9, 1.5 Hz, 1H), 7.30 (dd, J = 11.8, 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (t, J = 8.2 Hz, 1H), 5.10 (q, J = 7.1 Hz, 1H), 4.72 (br s, 1H), 4.43 — 4.29 (m, 2H), 1.93 (br s, 1H), 1.55 (d, J = 7.0 Hz, 3H), 0.78 (br s, 3H), 0.69 (br s, 3H). HRMS(B) (M+H) 28 Calc’d (M+H) 438.1941 331 & 332: (4S)—4- Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(4- chromatography (Column lA-H 5mM 20x250mm column ((tetrahydro—2H-pyran 30% MeOH) to give (S)isopropyl(2-(((R)—1-(4- yl)oxy)phenyl)ethyl)amino) ((tetrahydro-2H-pyran pyrimidinyl)oxazolidin- yl)oxy)phenyl)ethyl)amino)pyrimidinyl)oxazolidin 2-one one and (S)isopropyl(2-(((S)(4-((tetrahydro-2H- pyranyl)oxy)phenyl)ethyl)amino)pyrimidin yl)oxazolidinone. 1st peak 331: HRMS(B) (M+) 426.2267, RT = 2.45min 2nd peak 332: HRMS B M+ 426.2267, RT = 2.37min 333 & 334: (R)—3-(2-(1- Separation was ed on a normal phase silica gel (3,4- column with 10 to 40% ethylacetate/ heptane to give dichlorophenyl)ethylamino (R)(2-(((S)(3,4- idinyl) dichlorophenyl)ethyl)amino)pyrimidinyl)—4- phenyloxazolidinone phenyloxazolidinone and (R)—3-(2-(((R)—1-(3,4- dichlorophenyl)ethyl)amino)pyrimidinyl)—4- phenyloxazolidinone 1st peak 333:1H NMR (400 MHz, MeOD) 5 8.49 (d, J = .7 Hz, 1H), 7.85 — 7.74 (m, 5H), 7.74 — 7.68 (m, 1H), 7.66 — 7.61 (m, 2H), 7.55 (dd, J = 8.3, 2.1 Hz, 1H), 5.90 (dd, J = 8.9, 4.0 Hz, 1H), 5.14 (t, J = 8.7 Hz, 1H), 4.97 — 4.89 (m, 1H), 4.56 (dd, J = 8.8, 4.1 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 429.0899 Calc’d (M+H) 429.0885 2nd peak 334:1H NMR (400 MHz, MeOD) 5 8.50 (d, J = .7 Hz, 1H), 7.79 (d, J = 5.9 Hz,1H),7.61 (d, J = 8.4 Hz, 1H), 7.57 (dt, J = 4.6, 2.3 Hz, 3H), 7.45 (dd, J = 6.4, 2.9 Hz, 2H), 7.31 (dd, J = 8.3, 2.2 Hz, 1H), 6.16 (dd, J = 8.6, 3.5 Hz, 1H), 5.26 (q, J = 6.9 Hz, 1H), 5.16 (t, J = 8.6 Hz, 1H), 4.97 — 4.88 (m, 1H), 4.56 (dd, J = 8.8, 3.6 Hz, 1H), 1.80 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 429.0887 Calc’d M+H 429.0885 335 & 336: (S) Chiral separation was achieved by chiral SFC column pyl(2-(1-(4- chromatography (Column lA-H 5mM 20x250mm column (pyridin 40% MeOH, 10mM NH4OH) to give (S)isopropyl yl)phenyl)ethylamino)pyri (2-(((R)(4-(pyridinyl)phenyl)ethyl)amino)pyrimidin- midinyl)oxazolidin 4-yl)oxazolidinone and (S)isopropyl(2-(((S) one ridinyl)phenyl)ethyl)amino)pyrimidin yl)oxazolidinone. 1st peak 335: 1H NMR (400 MHz, MeOD) 5 8.81 (br s, 1H), 8.52 (br s, 1H), 8.14 (br s, 1H), 8.10 (dt, J = 8.2, 1.7 Hz, 1H), 7.71 — 7.59 (m, 2H), 7.58 — 7.46 (m, 3H), 7.37 (d, J = 5.8 Hz, 1H), 5.04 (dd, J = 11.2, 5.3 Hz,1H), 4.50 (br s, 1H), 4.40 — 4.19 (m, 2H), 2.69 (ddd, J = 10.4, 7.0, 3.5 Hz, 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 404.2085 Calc’d (M+H) 404.2086 oeak 336:1H NMR 400 MHz, MeOD 5 8.82 br s, 1H), 8.55 (br s, 1H), 8.17 (br s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.70 — 7.59 (m, 2H), 7.54 (br s, 1H), 7.51 — 7.45 (m, 2H), 7.38 (d, J = 5.7 Hz, 1H), 5.11 (q, J = 7.0 Hz, 1H), 4.66 (br s, 1H), 4.36 — 4.30 (m, 2H), 1.80 (br s, 1H), 1.58 (d, J = 7.0 Hz, 3H), 0.67 (br s, 3H), 0.56 (br s, 3H . HRMS B M+H 404.2079 Calc’d M+H 404.2086 337 & 338: (S) Separation was achieved on a normal phase silica gel isopropyl(2-(1-(4- column with 20 to 100% ethylacetate / heptane to give (pyridin (S)isopropyl(2-(((R)—1-(4-(pyridin yl)phenyl)ethylamino)pyri yl)phenyl)ethyl)amino)pyrimidinyl)oxazolidinone 4-yl)oxazolidin and (S)isopropyl(2-(((S)(4-(pyridin one yl)phenyl)ethyl)amino)pyrimidinyl)oxazolidinone. 1st peak 337: 1H NMR (400 MHz, MeOD) 6 8.58 (br s, 2H), 8.14 (d, J = 5.9 Hz, 1H), 7.83 — 7.66 (m, 4H), 7.60 — 7.46 (m, 2H), 7.37 (d, J = 5.8 Hz, 1H), 5.15 — 4.96 (m, 1H), 4.48 (br s, 1H), 4.38 — 4.15 (m, 2H), 2.69 (ddp, J = .5, 7.0, 3.5 Hz, 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 404.2068 Calc’d (M+H) 404.2086 2nd peak 338:1H NMR (400 MHz, MeOD) 6 8.59 (br s, 2H), 8.17 (br s, 1H), 7.80 — 7.68 (m, 4H), 7.56 — 7.44 (m, 2H), 7.38 (d, J = 5.8 Hz, 1H), 5.11 (q, J = 7.0 Hz, 1H), 4.65 (br s, 1H), 4.31 (dt, J = 17.1, 9.0 Hz, 2H), 1.76 (br s, 1H), 1.58 (d, J = 7.1 Hz, 3H), 0.66 (br s, 3H), 0.55 (br s, 3H). HRMS(B) (M+H) 404.1939 Calc’d (M+H) 404.2086 339 & 340: (S) Separation was ed on a normal phase silica gel isopropyl(2-(1-(4- column with 40 to 100% ethylacetate / heptane to give l(phenyl)amino)phe (S)isopropyl(2-(((R)—1-(4- nyl)ethylamino)pyrimidin- (methyl(phenyl)amino)phenyl)ethyl)amino)pyrimidin 4-yl)oxazolidinone yl)oxazolidinone and (S)isopropyl(2-(((S)(4- (methyl(phenyl)amino)phenyl)ethyl)amino)pyrimidin zolidinone. 1st peak 339: 1H NMR (400 MHz, MeOD) 6 8.12 (d, J = .8 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 7.31 — 7.18 (m, 4H), 7.03 — 6.94 (m, 4H), 6.91 (tt, J = 7.4, 1.1 Hz, 1H), 4.99 — 4.93 (m, 1H), 4.57 (br s, 1H), 4.42 — 4.27 (m, 2H), 3.28 (s, 3H), 2.68 (ddq, J = 10.5, 6.9, 3.4 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 432.2390 Calc’d (M+H) 432.2400 2nd peak 340: 1H NMR (400 MHz, MeOD) 6 8.15 (d, J = .8 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 7.30 — 7.18 (m, 4H), 7.02 — 6.92 (m, 4H), 6.89 (tt, J = 7.3, 1.1 Hz, 1H), .04 (q, J = 7.0 Hz, 1H), 4.77 — 4.67 (m, 1H), 4.43 — 4.26 (m, 2H), 3.27 (s, 3H), 2.11 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 0.79 (br s, 3H), 0.68 (br s, 3H). ) M+H 432.2386 Calc’d M+H 432.2400 341 & 342: S)—3-(2-(1-(3- Chiral separation was achieved by chiral SFC column fluoro(4-methyl-1H- (lC 20x250nm 45% IPA in CO2, 75g/min Flow) to give pyrazol (S)(2-(((R)—1-(3-fluoro(4-methyl-1 H-pyrazol yl)phenyl)ethylamino)pyri yl)phenyl)ethyl)amino)pyrimidinyl) midinyl) isopropyloxazolidinone and (S)(2-(((S)—1-(3-fluoro- isopropyloxazolidinone 4-(4-methyl-1H-pyrazol l ohen leth l amino 0 rimidin l isopropyloxazolidinone. 1st peak 341: 1H NMR (400 MHz, MeOD) 5 8.15 (d, J = .8 Hz, 1H), 7.81 (dt, J = 2.9, 0.9 Hz, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J = 5.8 Hz, 1H), 7.36 — 7.25 (m, 2H), 5.01 (d, J = 7.5 Hz, 1H), 4.46 (br s, 1H), 4.38 — 4.25 (m, 2H), 2.68 (pd, J = 7.0, 3.5 Hz, 1H), 2.17 (d, J = 0.6 Hz, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 425.2089 Calc’d (M+H) 425.2101 2nd peak 342: 1H NMR (400 MHz, MeOD) 5 8.17 (d, J = .8 Hz, 1H), 7.80 (d, J = 2.6 Hz, 1H), 7.66 (t, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J = 5.8 Hz, 1H), 7.35 — 7.26 (m, 2H), 5.10 (q, J = 7.0 Hz, 1H), 4.69 (br s, 1H), 4.43 — 4.24 (m, 2H), 2.17 (s, 3H), 1.80 (br s,1H), 1.56 (d, J = 7.1 Hz, 3H), 0.73 (br s, 3H), 0.62 (br s, 3H). HRMS(B) M+H 425.2081 Calc’d M+H 424.2101 343 & 344: (S)(2-(1-(4- Chiral separation was achieved by chiral SFC column imethyl-1H-pyrazol- chromatography (Column IA 20x250mm column 25% 1- MeOH, 0.2% DEA) to give (S)(2-(((R)(4-(3,5- y|)phenyl)ethylamino)pyri yl-1H-pyrazoly|)phenyl)ethyl)amino)pyrimidinmidiny |) 4-yl)isopropyloxazolidinone and (S)(2-(((S)—1- isopropyloxazolidinone (4-(3,5-dimethyl-1H-pyrazol yl)phenyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone. 1st peak 343:1H NMR (400 MHz, MeOD) 5 8.14 (d, J = .8 Hz, 1H), 7.56 — 7.48 (m, 2H), 7.41 — 7.34 (m, 3H), 6.06 (s, 1H), 5.07 — 5.02 (m, 1H), 4.46 (br s, 1H), 4.39 — 4.22 (m, 2H), 2.79 — 2.60 (m, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). ) (M+H) 421.2332 Calc’d (M+H) 421.2352 2nd peak 344:1H NMR (400 MHz, MeOD) 5 8.15 (d, J = .8 Hz, 1H), 7.55 — 7.47 (m, 2H), 7.41 — 7.33 (m, 3H), 6.06 (s, 1H), 5.17 (q, J = 7.0 Hz, 1H), 4.74 (br s,1H), 4.45 — 4.19 (m, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 2.07 (br s, 1H), 1.56 (d, J = 7.0 Hz, 3H), 0.80 (br s, 3H), 0.65 (br s, 3H). HRMS(B) (M+H) 421.2335 Calc’d (M+H) 421.2352 345 & 346: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(5- chromatography (AD-H , 5uM, 20x250 mm column , 80 methyl-1,3,4-oxadiazol ml/min, 99 bar, eluting 10% MeOH/CO2) to give (S) y|)ethy|)amino)pyrimidin isopropyl(2-(((R)—1-(5-methyl-1,3,4-oxadiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(5-methyl-1,3,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone. 1st peak 345: HRMS(B) m/z 333.1668 (M + H)+. 6 min. 2nd peak 346: HRMS(B) m/z 333.1668 (M + H)+.
RT=1.58 min. 347 & 348: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(1- tography (AD-H , 5uM, 20x250 mm column , 80 methyl-1H-1,2,4-triazol ml/min, 99 bar, eluting 10% MeOH/CO2) to give (S) y|)amino)pyrimidin isopropyl(2-(((R)—1-(1-methyl-1H-1,2,4-triazol y|)oxazolidinone. y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-is000ro l 2- S 1-meth l-1H-1,2,4-triazol yl)ethyl)amino)pyrimidinyl)oxazolidinone. 1st peak 347: HRMS(B) m/z 332.1831 (M + H)+.
RT=1.68 min. 2nd peak 348: HRMS(B) m/z 332.1833 (M + H)+.
RT=1.57 min. 349 & 350: (S)(2-((1- Chiral separation was achieved by chiral SFC column (imidazo[2,1- chromatography (AD-H , 5uM, 20x250 mm column , 80 b][1,3,4]thiadiazol ml/min, 99 bar, g 10% MeOH/CO2) to give (S) y|)ethy|)amino)pyrimidin (2-(((R)(imidazo[2,1-b][1,3,4]thiadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one. one and (S)(2-(((S)—1-(imidazo[2,1-b][1,3,4]thiadiazol- 6-yl)ethyl)amino)pyrimidinyl)isopropyloxazolidin one. 1st peak 349: HRMS(B) m/z 374.1384 (M + H)+. 1 min. 2nd peak 350: 1H NMR (400 MHz, CDCI3) 5 8.43 (s, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.60 (s, 1H), 7.38 (d, J = .8 Hz, 1H), 5.13 (s, 1H), 4.60 (dt, J = 8.3, 3.3 Hz, 1H), 4.33 — 4.07 (m, 2H), 2.25 (b, 1H), 1.57 (d, J = 6.8 Hz, 3H), 0.84 — 0.52 (b, 6H). HRMS(B) m/z 373.1321 (M +), RT=1.88 min. 351 & 352: (S)(2-((1-(1- Chiral tion was achieved by chiral SFC column ethyl-1H-1,2,4-triazol chromatography (AD-H , 5uM, 20x250 mm column , 80 y|)ethy|)amino)pyrimidin ml/min, 99 bar, eluting 10% MeOH/CO2) to give (S) isopropyloxazolidin- (2-(((R)(1-ethyl-1H-1,2,4-triazol 2-one y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin one and (S)(2-(((S)(1-ethy|-1H-1,2,4-triazol y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 351: HRMS(B) m/z 346.1985 (M + H)+.
RT=1.89 min. 2nd peak 352: HRMS(B) m/z 346.1983 (M + H)+, RT=1.75 min. 353 & 354: (S)(2-((1-(4- Chiral separation was achieved by chiral SFC column ethyl-4H-1,2,4-triazol chromatography (AD-H , 5uM, 20x250 mm column , 80 y|)ethy|)amino)pyrimidin , 99 bar, eluting 10% O2) to give (S) yl)isopropyloxazolidin- (2-(((R)(4-ethyl-4H-1,2,4-triazol 2-one y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin one and (S)(2-(((S)(4-ethy|-4H-1,2,4-triazol y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 353: HRMS(B) m/z 346.1984 (M + H)+.
RT=1.80 min. 2nd peak 354:HRMS(B) m/z 346.1982 (M + H)+, RT=1.77 min. 355 & 356: (2-((1- Chiral separation was achieved by chiral SFC column (imidazo[2,1-b]thiazol chromatography (AD-H , 5uM, 20x250 mm column , 75 y|)ethy|)amino)pyrimidin , 120 bar, eluting 20-30% MeOH/CO2) to give yl)isopropyloxazolidin- (S)(2-(((R)(imidazo[2,1-b]thiazol 2-one y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin one and (S)(2-(((S)—1-(imidazo[2,1-b]thiazol y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 355: HRMS(B) m/z 373.1436 (M + H)+.
RT=1.92 min. 2nd peak 356: HRMS(B) m/z 373.1439 (M +H)+, RT=1.84 min. 357 & 358: 1-((4- Chiral separation was achieved by chiral SFC column -isopropyl chromatography (AD-H , 5uM, 20x250 mm column , 80 oxooxazolidin ml/min, 96 bar, eluting 25% MeOH/CO2) to give N-(4- yl)pyrimidin ((R)—1-((4-((S)isopropyloxooxazolidin yl)amino)ethyl)phenyl)met imidin hanesulfonamide no)ethyl)phenyl)methanesulfonamide and N-(4- ((S)((4-((S)isopropyloxooxazolidin yl)pyrimidin yl)amino)ethyl)phenyl)methanesulfonamide 1st peak 357: HRMS(B) m/z 420.1689 (M + H)+.
RT=2.08 min. 2nd peak 358: HRMS(B) m/z 420.1687 (M +H)+, RT=1.98 min. 359 & 360: (S) tion was achieved by silica gel chromatography isopropyl(2-((1-(3- (10 to 40% EtOAc / heptane) to give (S)isopropyl (pyridinyl)—1,2,4- (2-(((R)(3-(pyridinyl)-1,2,4-oxadiazol oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone and (S)- yl)ethyl)amino)pyrimidin 4-isopropyl(2-(((S)—1-(3-(pyridinyl)-1,2,4-oxadiazolyl )oxazolidinone 5-yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 359: HRMS(B) m/z 396.1784 (M + H)+.
RT=2.26 min. 2nd peak 360: HRMS(B) m/z 84 (M +H)+, RT=2.20 min. 361 & 362: (S) Separation was achieved by silica gel chromatography isopropyl(2-((1-(3-(p- (10 to 40% EtOAc / heptane) to give (S)isopropyl toly|)-1,2,4-oxadiazol (2-(((R)(3-(p-tolyl)-1,2,4-oxadiazol yl)ethyl)amino)pyrimidin yl)ethyl)amino)pyrimidinyl)oxazolidinone and (S)- yl)oxazolidinone 4-isopropyl(2-(((S)—1-(3-(p-tolyl)-1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone. 1st peak 361: HRMS(B) m/z 409.1985 (M + H)+.
RT=2.88 min. 2nd peak 362:1H NMR (400 MHz, CDCI3) 6 8.24 (d, J = .8 Hz, 1H), 8.03 (d, J = 5.9 Hz, 2H), 7.59 (d, J = 5.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 5.41 (b, 1H), 4.67 (dt, J = 8.2, 3.3 Hz, 1H), 4.36 — 4.18 (m, 2H), 2.42 (s, 3H), 2.29 — 2.13 (m, 1H), 1.78 (d, J = 7.2 Hz, 3H), 0.81 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H). HRMS(B) m/z 409.1985 M +H +, RT=2.85 min. 363 & 364: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(4- chromatography (AD-H 20x250 mm column 74 , 5uM, , (methylsulfonyl)phenyl)eth ml/min, 100 bar, eluting 25% MeOH/CO2) to give (S) yl)amino)pyrimidin isopropyl(2-(((R)—1-(4- yl)oxazolidinone (methylsulfonyl)phenyl)ethyl)amino)pyrimidin yl)oxazolidinone and isopropyl(2-(((S)—1-(4- (methylsulfonyl)phenyl)ethyl)amino)pyrimidin yl)oxazolidinone 1st peak 363: HRMS(B) m/z 405.1594 (M + H)+.
RT=2.26 min. 2nd peak 364: HRMS(B) m/z 405.1595 (M +H)+, 4 min. 365 & 366: (S) Chiral separation was achieved by chiral SFC column pyl(2-((1-(3- chromatography (AD-H , 5uM, 20x250 mm column , 80 meth l-1,2,4-oxadiazol ml/min, 100 bar, elutino 20% IPA/CO2 to ' y|)ethy|)amino)pyrimidin isopropyl(2-(((R)(3-methy|-1,2,4-oxadiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- ropyl(2-(((S)(3-methyl-1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 365: ) m/z 333.1679 (M + H)+.
RT=2.19 min. 2nd peak 366: HRMS(B) m/z 333.1680 (M +H)+, RT=2.12 min. 367 & 368: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column ethylisoxazol chromatography (AD-H , 5uM, 20x250 mm column , 79 y|)ethy|)amino)pyrimidin ml/min, 100 bar, eluting 20% IPA/CO2) to give (2- yl)isopropyloxazolidin- (((R)—1-(3-ethy|isoxazolyl)ethyl)amino)pyrimidinyl)— 2-one 4-isopropyloxazolidinone and (S)(2-(((S)—1-(3- ethylisoxazolyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 367: HRMS(B) m/z 346.1886 (M + H)+.
RT=2.51 min. 2nd peak 368: HRMS(B) m/z 346.1882 (M +H)+, RT=2.45 min. 369 & 370: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3- chromatography (AD-H , 5uM, 20x250 mm column , 75 propyl-1,2,4-oxadiazol ml/min, 100 bar, eluting 20% IPA/CO2) to give (S) y|)ethy|)amino)pyrimidin isopropyl(2-(((R)(3-propy|-1,2,4-oxadiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(3-propyl-1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 369: HRMS(B) m/z 361.1989 (M + H)+.
RT=2.52 min. 2nd peak 370: HRMS(B) m/z 361.1985 (M +H)+, RT=2.49 min. 371 & 372: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column cyclopropyl-1,2,4- chromatography (AD-H , 5uM, 20x250 mm column , 80 oxadiazol ml/min, 100 bar, eluting 15% IPA/CO2) to give (S)(2- y|)ethy|)amino)pyrimidin (((R)—1-(3-cyclopropyl-1,2,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(3-cyc|opropyl-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)isopropyloxazolidin 1st peak 371: HRMS(B) m/z 359.1830 (M + H)+. 2 min. 2nd peak 372: HRMS(B) m/z 33 (M +H)+, RT=2.37 min. 373 & 374: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3- chromatography (AD-H , 5uM, 20x250 mm column , 80 isopropyl-1,2,4-oxadiazol- ml/min, 100 bar, eluting 20% IPA/CO2) to give (S) thyl)amino)pyrimidin- isopropyl(2-(((R)(3-isopropy|-1,2,4-oxadiazol 4-yl)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(3-isopropyl-1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 373: HRMS(B) m/z 90 (M + H)+. 8 min. 2nd peak 374: HRMS(B) m/z 361.1987 (M +H)+, RT=2.54 min. 375 & 376: (S)(2-((1-(1- Chiral separation was achieved by chiral SFC column eth l-1H-p razol chromato-raph AD-H , 5uM, 20x250 mm column , 78 y|)ethy|)amino)pyrimidin ml/min, 100 bar, g 20% IPA/CO2) to give (S)(2- yl)isopropyloxazolidin- 1-(1-ethyl-1H-pyrazolyl)ethyl)amino)pyrimidin 2-one y|)isopropyloxazolidinone and (S)(2-(((S)—1-(1- ethyl-1H-pyrazolyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 375: HRMS(B) m/z 345.2046 (M + H)+.
RT=2.31 min. 2nd peak 376: HRMS(B) m/z 345.2050 (M +H)+, RT=2.26 min. 377 & 378: (S)(2-((1-(2- Chiral separation was achieved by chiral column hydroxyphenyl)ethyl) chromatography (OJ-H 4.6x250 mm column 1 , , amino)pyrimidinyl)—4- ml/min, eluting 25% ethanol /Heptane) to give (S)(2- pyloxazolidinone (((R)—1-(2-hydroxyphenyl)ethyl)amino)pyrimidinyl)—4- isopropyloxazolidinone and (S)(2-(((S)—1-(2- hydroxyphenyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 377: HRMS(B) m/z 343.1767 (M + H)+.
RT=2.41 min. 2nd peak 378: HRMS(B) m/z 343.1767 (M +H)+, RT=2.36 min. 379 & 380: (S) Chiral separation was achieved by chiral SFC column pyl(2-((1-(5- chromatography (AD-H , 5uM, 20x250 mm column , methylphenyl-1H-1,2,3- 874ml/min, 100 bar, g 30% IPA/CO2) to give (8)- l 4-isopropyl(2-(((R)(5-methy|phenyl-1H-1,2,3- y|)amino)pyrimidin triazolyl)ethyl)amino)pyrimidinyl)oxazolidinone y|)oxazolidinone and (S)isopropyl(2-(((S)(5-methy|phenyl-1H- 1,2,3-triazolyl)ethyl)amino)pyrimidinyl)oxazolidin- 2-one 1st peak 379: HRMS(B) m/z 408.2135 (M + H)+.
RT=2.37 min. 2nd peak 380: ) m/z 408.2140 (M +H)+, RT=2.31 min. 381 & 382: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3- chromatography (AD-H , 5uM, 20x250 mm column 74 phenyl-1,2,4-oxadiazol ml/min, 100 bar, eluting 20% -35% IPA/CO2) to give y|)ethy|)amino)pyrimidin (S)isopropyl(2-(((R)—1-(3-phenyl-1,2,4-oxadiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(3-phenyl-1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 381: HRMS(B) m/z 395.1792 (M + H)+.
RT=2.63 min. 2nd peak 382: HRMS(B) m/z 395.1818(M +H)+, RT=2.58min. 383 & 384: (S)(2-(((R)— Chiral separation was achieved by chiral SFC column 1-(1H-pyrrolo[2,3- chromatography (IA, 20x250 mm column 74 ml/min, din 99 bar, eluting 45% MeOH with 5mM NH4OH /CO2) to y|)ethy|)amino)pyrimidin give (S)(2-(((R)—1-(1H-pyrrolo[2,3-b]pyridin yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(1H-pyrrolo[2,3-b]pyridin y|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 383: HRMS(B) m/z 367.1862 (M + H)+.
RT=2.10 min. 2nd peak 384:1H NMR (400 MHz, CDCI3) 6 8.32 (d, J = 2.2 Hz, 1H , 8.19 d, J = 5.8 Hz, 1H , 7.94 d, J = 2.1 Hz, 1H), 7.47 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 3.5 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 5.30 — 5.08 (m, 1H), 4.73 — 4.51 (m, 1H), 4.28 (t, J = 8.8 Hz, 1H), 4.19 (dd, J = 9.0, 3.1 Hz, 1H), 1.78 (dd, J = 318,170 Hz, 1H), 1.66 (d, J = 6.9 Hz, 3H), 0.56 (s, 6H). HRMS(B) m/z 367.1870 M +H +, 0min. 385 & 386: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(1- chromatography (AD-H , 5uM, 20x250 mm column , 80 methyl-1H- ml/min, 99 bar, eluting 20% IPA/CO2) to give (S) benzo[d]imidazol isopropyl(2-(((R)(1-methyl-1H-benzo[d]imidazol y|)ethy|)amino)pyrimidin y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- y|)oxazolidinone 4-isopropyl(2-(((S)(1-methyl-1H-benzo[d]imidazol- -yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 385: HRMS(B) m/z 381.2026 (M + H)+.
RT=2.05 min. 2nd peak 386: HRMS(B) m/z 22(M +H)+, RT=1.96min. 387 & 388: (S) Chiral tion was achieved by chiral SFC column isopropyl(2-((1-(2-oxo- chromatography (AD-H , 5uM, 20x250 mm column , 80 2,3—dihydro—1 H- ml/min, 100 bar, eluting 25% IPA/CO2) to give (S) benzo[d]imidazol isopropyl(2-(((R)(2-oxo-2,3-dihydro-1H- y|)ethy|)amino)pyrimidin benzo[d]imidazolyl)ethyl)amino)pyrimidin y|)oxazolidinone y|)oxazolidinone and (S)—4—isopropyl(2-(((S)(2- oxo-2,3-dihydro-1H-benzo[d]imidazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 387: HRMS(B) m/z 383.1811 (M + H)+.
RT=1.90 min. 2nd peak 388: HRMS(B) m/z 383.1815(M +H)+, RT=1.85min. 389 & 390: (S)(2-((1- Chiral separation was achieved by chiral SFC column (benzo[d]thiazol chromatography (ID, 5uM, 20x250 mm column 74 y|)ethy|)amino)pyrimidin ml/min, 100 bar, eluting H/CO2) to give (S) yl)isopropyloxazolidin- R)(benzo[d]thiazolyl)ethyl)amino)pyrimidin 2-one y|)isopropyloxazolidinone and (S)(2-(((S)—1- [d]thiazolyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone 1st peak 389: HRMS(B) m/z 384.1488 (M + H)+. 4 min. 2nd peak 390: HRMS(B) m/z 384.1473(M +H)+, RT=2.36min. 391 & 392: (S)(2-((1- Chiral separation was achieved by chiral SFC column (indolizin chromatography (OJ mm column , 5uM, 20x250 , 75 y|)amino)pyrimidin ml/min, 120 bar, eluting 15-55% MeOH/CO2) to give isopropyloxazolidin- (S)(2-(((R)—1-(indolizinyl)ethyl)amino)pyrimidin 2-one y|)isopropyloxazolidinone and (S)(2-(((S)—1- (indolizinyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 391: HRMS(B) m/z 366.1926 (M + H)+.
RT=2.66 min. 2nd peak 392: HRMS(B) m/z 366.1918(M +H)+, RT=2.63min. 393 & 394: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3-(2- chromatography (AD-H mm column , 5uM, 20x250 , 80 methoxyphenyl)-1,2,4- ml/min, 100 bar, eluting 5-55% MeOH/CO2) to give (8)- oxadiazol rop l 2- R 3— 2-methox phen l -1,2,4- y|)ethy|)amino)pyrimidin oxadiazolyl)ethyl)amino)pyrimidinyl)oxazolidin y|)oxazolidinone one and (S)isopropyl(2-(((S)(3-(2- methoxyphenyl)—1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 393: HRMS(B) m/z 425.1925 (M + H)+.
RT=2.57 min. 2nd peak 394: HRMS(B) m/z 425.1916(M +H)+, RT=2.52min. 395 & 396: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3-(3- chromatography (IA, 5uM, 20x250 mm column 74 methoxyphenyl)-1,2,4- ml/min, 100 bar, eluting m25% MeOH/CO2) to give (8)- oxadiazol 4-isopropyl(2-(((R)(3-(3-methoxyphenyl)-1,2,4- y|)ethy|)amino)pyrimidin oxadiazolyl)ethyl)amino)pyrimidinyl)oxazolidin y|)oxazolidinone one and isopropyl(2-(((S)(3-(3- methoxyphenyl)—1,2,4-oxadiazol yl)amino)pyrimidinyl)oxazolidinone 1st peak 395: ) m/z 425.1924 (M + H)+.
RT=2.60 min. 2nd peak 396:1H NMR (400 MHz, CDCI3) 5 7.56 (dt, J = 7.7, 1.2 Hz, 1H), 7.49 (dt, J = 3.7, 1.8 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 6.96 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 5.34 (b, 1H), 4.58 (dt, J = 8.2, 3.3 Hz, 1H), 4.37 — 4.03 (m, 2H), 3.78 (s, 3H), 2.12 (b, 1H), 1.68 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H), 0.65 (d, J = 7.0 Hz, 3H).
HRMS B m/z 425.1924 M +H +, RT=2.54min. 397 & 398: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column (3-fluorophenyl)-1,2,4- chromatography (AD-H , 5uM, 20x250 mm column , 75 oxadiazol ml/min, 100 bar, eluting 20% MeOH/CO2) to give (S) y|)ethy|)amino)pyrimidin (2-(((R)(3-(3-fluorophenyl)-1,2,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (2-(((S)—1-(3-(3-fluorophenyl)-1,2,4- oxadiazolyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 397: HRMS(B) m/z 413.1729 (M + H)+.
RT=2.66 min. 2nd peak 398: 1H NMR (400 MHz, CDCI3) 5 7.86 (dt, J = 7.8, 1.2 Hz, 1H), 7.77 (ddd, J = 9.4, 2.7, 1.5 Hz, 2H), 7.60 (d, J = 5.3 Hz, 1H), 7.46 (td, J = 8.0, 5.7 Hz,1H), 7.22 (tdd, J = 8.4, 2.6, 1.0 Hz, 1H), 5.44 (b, 1H), 4.68 (dt, J = 8.3, 3.3 Hz, 1H), 4.44 — 4.11 (m, 2H), 2.18 (d, J = 8.4 Hz, 1H), 1.78 (d, J = 7.1 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H). HRMS(B) m/z 413.1732 M +H +, RT=2.61min. 399 & 400: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column cyclopentyl-1,2,4- chromatography (IA 20x250 mm column 74 , 5uM, , zol ml/min,99 bar, eluting 15% MeOH/CO2) to give (S) y|)ethy|)amino)pyrimidin (2-(((R)(3-cyclopentyl-1,2,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (2-(((S)—1-(3-cyc|opentyl-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)isopropyloxazolidin 1st peak 399: ) m/z 387.2133 (M + H)+.
RT=2.54 min. 2nd peak 400: HRMS(B) m/z 387.2117(M +H)+, RT=2.50min. 401 & 402: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column cyclohexyl-1,2,4- chromatography (IA, 5uM, 20x250 mm column 74 oxadiazol ml/min, 99 bar, g 30% MeOH/CO2) to give (S) y|)ethy|)amino)pyrimidin (2-(((R)(3-cyclohexyI-1,2,4-oxadiazoI isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(3-cyclohexyl-1,2,4-oxadiazol- thyl)amino)pyrimidinyl)isopropyloxazolidin 1st peak 401: HRMS(B) m/z 401.2277 (M + H)+.
RT=2.71 min. 2nd peak 402: ) m/z 401.2288(M +H)+, RT=2.68min. 403 & 404: (S)(2-((1-(3- Chiral separation was ed by chiral SFC column (tert-butyl)-1,2,4- chromatography (IA, 5uM, 20x250 mm column 74 oxadiazol ml/min, 100 bar, eluting 15% O2) to give (S) y|)ethy|)amino)pyrimidin (2-(((R)(3-(tert-butyl)-1,2,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(3-(tert-butyl)-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)isopropyloxazolidin 1st peak 403: HRMS(B) m/z 375.2131 (M + H)+.
RT=2.47 min. 2nd peak 404: HRMS(B) m/z375.2130 (M +H)+, RT=2.44min. 405 & 406: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column isobutyl-1,2,4-oxadiazol chromatography (IA, 5uM, 20x250 mm column 74 y|)ethy|)amino)pyrimidin ml/min, 100 bar, eluting 15% MeOH/CO2) to give (S) yl)isopropyloxazolidin- (2-(((R)(3-isobutyl-1,2,4-oxadiazol 2-one y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin one and (S)(2-(((S)—1-(3-isobutyl-1,2,4-oxadiazol y|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 405: HRMS(B) m/z 375.2120 (M + H)+.
RT=2.45 min. 2nd peak 406: HRMS(B) m/z 375.2135 (M +H)+, RT=2.44min. 407 & 408: (S)(2-((1-(5- Chiral tion was achieved by chiral SFC column (4-fluorophenyl)-1,3,4- chromatography (IA, 5uM, 20x250 mm column 74 oxadiazol ml/min, 99 bar, eluting 30% IPA/CO2) to give (S)(2- y|)ethy|)amino)pyrimidin (((R)—1-(5-(4-fluorophenyl)-1,3,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(5-(4-fluorophenyl)-1,3,4- zolyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 407: HRMS(B) m/z 413.1713 (M + H)+.
RT=2.31 min. 2nd peak 408: HRMS(B) m/z 413.1721 (M +H)+, RT=2.25min. 409 & 410: (S)(2-((1- Chiral separation was achieved by chiral SFC column (benzo[d]oxazol chromatography (IA, 5uM, 20x250 mm column 74 y|)ethy|)amino)pyrimidin ml/min, 99 bar, eluting 25% O2) to give (S) yl)isopropyloxazolidin- (2-(((R)(benzo[d]oxazolyl)ethyl)amino)pyrimidin 2-one y|)isopropyloxazolidinone and (S)(2-(((S)—1- (benzo[d]oxazolyl)ethyl)amino)pyrimidinyl)—4- is000ro onazolidinone 1st peak 409: HRMS(B) m/z 368.1729 (M + H)+.
RT=2.66 min. 2nd peak 410: 1H NMR (400 MHz, CDCI3) 5 7.80 — 7.61 (m, 1H), 7.54 (s, 1H), 7.51 — 7.42 (m, 2H), 7.40 — 7.21 (m, 2H), 6.40 (b, 1H), 5.39 (s, 1H), 4.64 (dt, J = 8.1, 3.2 Hz, 1H), 4.36 — 4.17 (m, 2H), 2.11 (b, 1H), 1.77 (d, J = 6.9 Hz, 3H), 0.64 (b, 6H). HRMS(B) m/z 368.1727 (M +H +, 0min. 411 & 412: (2-((1-(4- Separation was ed by silica gel chromatography orophenyl)—5- (10 to 50% EtOAc/ heptane) to give (S)(2-(((R)(4- methylthiazol (4-chlorophenyl)methylthiazol y|)ethy|)amino)pyrimidin y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin yl)isopropyloxazolidin- one and (S)—3-(2-(((S)—1-(4-(4-ch|orophenyl) 2-one methylthiazolyl)ethyl)amino)pyrimidinyl) pyloxazolidinone 1st peak 411: HRMS(B) m/z 458.1401 (M + H)+.
RT=3.02 min. 2nd peak 412: HRMS(B) m/z 458.1401 (M +H)+, RT=2.92min. 413 & 414: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column ethyl-1,2,4-oxadiazol chromatography (AD-H column (80 g/min, 80 bar, 20 X y|)ethy|)amino)pyrimidin 250 mm) eluting 15% MeOH/CO2) to give (S)(2- yl)isopropyloxazolidin- (((R)—1-(3-ethyl-1,2,4-oxadiazol 2-one y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin one and (S)—3-(2-(((S)—1-(3-ethy|-1,2,4-oxadiazol y|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 413: HRMS(B) m/z 346.1753 RT=2.13 min. oeak 414: HRMS B m/z 346.1753 5 min. 415 & 416: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(4- chromatography (AD-H column (75 ml/min, 120 bar, 20 methylthiazol x 250 mm) eluting 10-25% MeOH/CO2) to give (S)—4- y|)ethy|)amino)pyrimidin isopropyl(2-(((R)(4-methy|thiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(4-methylthiazol yl)amino)pyrimidinyl)oxazolidinone 1st peak 415: HRMS(B) m/z 347.1416 RT=2.25 min. 2nd peak 416: HRMS B m/z 347.1416 RT=2.17 min. 417 & 418: (S) Chiral tion was achieved by chiral SFC column isopropyl(2-((1- tography (AD-H column (75 ml/min, 120 bar, 20 (thiophen x 250 mm) eluting 10-25% MeOH/CO2) to give (S)—4- y|)ethy|)amino)pyrimidin isopropyl(2-(((R)(thiophen y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(thiophen yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 417: HRMS(B) m/z 332.1307 RT=2.54 min. 2nd peak 418: HRMS B m/z 332.1307 RT=2.53 min. 419 & 420: (S)(2-((1- Chiral separation was achieved by chiral SFC column (furan chromatography (AD-H column (75 ml/min, 120 bar, 20 y|)ethy|)amino)pyrimidin x 250 mm) eluting 10-25% MeOH/CO2) to give (S)—3- yl)isopropyloxazolidin- (2-(((S)(furanyl)ethyl)amino)pyrimidiny|) 2-one isopropyloxazolidinone and (S)(2-(((R)—1-(furan y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 419: HRMS B m/z 316.1535 RT=2.37 min. 2nd peak 420: HRMS B m/z 316.1535 RT=2.39 min. 421 & 422: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3- chromatography (IA column (75 ml/min, 120 bar, 20 x (pyridinyl)—1,2,4- 250 mm) eluting 15-25% MeOH/CO2) to give (S)—4- oxadiazol isopropyl(2-(((R)—1-(3-(pyridinyl)-1,2,4-oxadiazol y|)ethy|)amino)pyrimidin y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- y|)oxazolidinone 4-isopropyl(2-(((S)(3-(pyridinyl)-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 421: HRMS(B) m/z 395.1706 RT=1.75 min. 2nd peak 422: HRMS B m/z 395.1706 RT=2.25 min. 423 & 424: (2-((1-(3- Chiral separation was ed by chiral SFC column (2-chlorophenyl)—1,2,4- chromatography (IA column (75 ml/min, 120 bar, 20 x oxadiazol 250 mm) eluting 15-25% MeOH/CO2) to give (S)—3-(2- y|)ethy|)amino)pyrimidin 1-(3-(2-chlorophenyl)-1,2,4-oxadiazoI isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(3-(2-chloropheny|)-1,2,4- oxadiazolyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone 1st peak 423: HRMS(B) m/z 64 RT=3.01 min. 2nd peak 424: HRMS B m/z 428.1364 RT=2.79 min. 425 & 426: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column (4-chlorophenyl)—1,2,4- chromatography (IA column (75 ml/min, 120 bar, 20 x oxadiazol 250 mm) eluting 15-25% MeOH/CO2) to give (S)—3-(2- y|)ethy|)amino)pyrimidin (((R)—1-(3-(4-chlorophenyl)-1,2,4-oxadiazoI yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (2-(((S)—1-(3-(4-chloropheny|)-1,2,4- oxadiazolyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone 1st peak 425: HRMS(B) m/z 428.1364 RT=2.65 min. 2nd peak 426:1H NMR (400 MHz, MeOD) 5 8.22 (d, J = .8 Hz, 1.0H), 8.08 — 7.97 (m, 2.07 H), 7.63 — 7.40 (m, 3.09 H), 5.41 (q, J = 7.2 Hz, 1.04 H), 4.75 — 4.63 (m, 0.97 H), 4.33 (d, J = 6.3 Hz, 2.18 H), 1.76 (d, J = 7.2 Hz, 3.31 H), 1.07 — 0.85 (m, 0.95 H), 0.70 (d, J = 38.0 Hz, .81 H . HRMS B m/z 64 427: (S)isopropyI(2- Chiral separation was achieved by chiral SFC column ((1-(3-(pyridinyl)-1,2,4- chromatography (IA column (75 ml/min, 120 bar, 20 x oxadiazol 250 mm) eluting 15-25% MeOH/CO2) to give (S) y|)ethy|)amino)pyrimidin isopropyl(2-(((R)—1-(3-(pyridinyl)-1,2,4-oxadiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(3-(pyridinyl)-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)oxazolidinone 2nd peak 427: HRMS B m/z 395.1706 RT=2.24 min. 428 & 429: (S)(2-((1-(1- Chiral separation was achieved by chiral SFC column ethyl-1H-pyrazol tography (AD column (75 g/min, 120 bar, 20 x y|)ethy|)amino)pyrimidin 250 mm) g 25% IPA/0.2% DEA/CO2) to give (8)- yl)isopropyloxazolidin- ((R)—1-(1-ethyI-1H-pyrazol 2-one y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin one and (S)—3-(2-(((S)(1-ethyl-1H-pyrazol y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 1st peak 428: HRMS(B) m/z 345.2005 (M+H) RT=2.28 mIn. 2nd peak 429: HRMS(B) m/z 345.2044 (M+H) RT=2.21 mIn. 430: (S)isopropyl(2- Chiral separation was achieved by chiral SFC column (((S)(3-(m-tolyl)-1,2,4- chromatography (AD column (75 g/min, 120 bar, 20 x oxadiazol 250 mm) eluting 25-35% 2% DEA/CO2) to give y|)ethy|)amino)pyrimidin (S)isopropyl(2-(((R)(3-(m-to|yl)-1,2,4-oxadiazol- y|)oxazolidinone 5-yl)ethyl)amino)pyrimidinyl)oxazolidinone and (S)isopropyl(2-(((S)(3-(m-toly|)-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)oxazolidinone 2nd peak 430: HRMS(B) m/z 345.2044 (M+H) RT=2.82 mIn. 431 & 432: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(2- chromatography (AD column (75 g/min, 120 bar, 20 x phenylthiazol 250 mm) g 40% IPA/0.2% DEA/CO2) to give (8)- y|)ethy|)amino)pyrimidin 4-isopropyl(2-(((R)(2-pheny|thiazol y|)oxazolidinone y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((S)(2-phenylthiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 431: HRMS(B) m/z 409.1573 RT=2.33 min. 2nd peak 432:1H NMR (400 MHz, MeOD) 5 8.19 (d, J = .8 Hz, 1H), 7.92 — 7.78 (m, 2H), 7.65 (d, J =1.1 Hz, 1H), 7.53 — 7.27 (m, 4H), 5.43 (q, J = 6.9 Hz, 1H), 4.74 (dt, J = 7.8, 3.7 Hz, 1H), 4.41 — 4.20 (m, 2H), 2.16 (s, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 6.1 Hz,1H), 0.88 — 0.49 m, 6H . HRMS B m/z 409.1573 433 & 434: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3-(o- chromatography (AD column (75 g/min, 120 bar, 20 x -1,2,4-oxadiazol 250 mm) eluting 25-40% IPA/0.2% DEA/CO2) to give y|)ethy|)amino)pyrimidin (S)isopropyl(2-(((R)(3-(o-to|y|)-1,2,4-oxadiazoly |)oxazolidinone 5-yl)ethyl)amino)pyrimidinyl)oxazolidinone and (S)isopropy|(2-(((S)(3-(o-to|y|)-1,2,4-oxadiazol- -yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 433: ) m/z 409.1 (M+H) RT=2.25 min. 2nd peak 434:1H NMR (400 MHz, MeOD) 5 8.20 (d, J = .8 Hz, 1H), 7.90 (dd, J = 7.7,1.4 Hz, 1H), 7.47 (d, J = .8 Hz, 1H), 7.41 — 7.25 (m, 3H), 5.40 (q, J = 7.2 Hz, 1H), 4.69 (s, 1H), 4.44 — 4.22 (m, 2H), 3.34 (s, 2H), 2.54 (s, 3H), 1.75 (d, J = 7.2 Hz, 3H), 1.15 (d, J = 6.1 Hz, 1H), 0.69 (d, J = 35.0 Hz, 6H). HRMS(B) m/z 409.1 435 & 436: 4-(1-((4-((S) Chiral separation was ed by chiral SFC column isopropyloxooxazolidin- tography (AS-H column (80 g/min, 120 bar, 20 x 3-yl)pyrimidin 250 mm) eluting 15% IPA/0.2% DEA/CO2) to give 4- y|)amino)ethyl)-N,N- ((R)—1-((4-((S)isopropyloxooxazolidin dimethylbenzenesulfonam y|)pyrimidinyl)amino)ethyl)—N,N- ide dimethylbenzenesulfonamide and 4-((S)((4-((S)—4- isopropyloxooxazolidinyl)pyrimidin y|)amino)ethyl)-N,N-dimethylbenzenesulfonamide 1st peak 435: HRMS(B) m/z 84 RT=2.45 min. oeak 436: HRMS B m/z 84 RT=2.32 min. 437 & 438: (S) Chiral separation was ed by chiral SFC column isopropyl(2-((1-(thiazol- chromatography (lC column (75 g/min, 120 bar, 20 x 4-yl)ethyl)amino)pyrimidin- 250 mm) eluting 25% IPA/0.2% DEA/CO2) to give (8)- 4-yl)oxazolidinone 4-isopropyl(2-(((S)(thiazol y|)ethy|)amino)pyrimidinyl)oxazolidinone and (S)- 4-isopropyl(2-(((R)(thiazol l eth l amino 0 rimidin l oxazolidinone 1st peak 437: HRMS(B) m/z 333.1259 RT=1.88 min. 2nd peak 438: HRMS B m/z 333.1259 8 min. 439 & 440: (S) Chiral separation was achieved by chiral SFC column isopropyl(2-((1-(3-(4- chromatography (Al column (70 g/min, 120 bar, 20 x yphenyl)-1,2,4- 250 mm) eluting 20% IPA/0.2% DEA/CO2) to give (8)- oxadiazol 4-isopropyl(2-(((R)(3-(4-methoxyphenyl)-1,2,4- y|)ethy|)amino)pyrimidin oxadiazolyl)ethyl)amino)pyrimidinyl)oxazolidin y|)oxazolidinone one and (S)isopropyl(2-(((S)(3-(4- yphenyl)—1,2,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone 1st peak 438: ) m/z 425.1921 (M+H) 9 min. 2nd peak 439: HRMS(B) m/z 425.1923 (M+H) RT=2.42 min. 441 & 442: (S)(2-((1-(3- Chiral separation was achieved by chiral SFC column (4-fluorophenyl)-1,2,4- chromatography (Al column (70 g/min, 120 bar, 20 x oxadiazol 250 mm) eluting 25% IPA/0.2% 2) to give (8)- y|)ethy|)amino)pyrimidin 3-(2-(((R)(3-(4-fluorophenyl)-1,2,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(3-(4-fluorophenyl)-1,2,4- oxadiazolyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone 1st peak 441: HRMS(B) m/z 413.1719 (M+H) RT=2.58 min. 2nd peak 442: HRMS(B) m/z 413.1719 (M+H) RT=2.52 min. 443: (S)(2-(((S)(5-(4- Chiral separation was achieved by chiral SFC column phenyl)—1,2,4- chromatography (ID-H column (80 g/min, 120 bar, 20 x oxadiazol 250 mm) eluting 30% MeOH/CO2) to give (S)(2- y|)ethy|)amino)pyrimidin (((R)—1-(5-(4-ch|orophenyl)-1,2,4-oxadiazol yl)isopropyloxazolidin- y|)ethy|)amino)pyrimidinyl)isopropyloxazolidin 2-one one and (S)(2-(((S)—1-(5-(4-ch|oropheny|)-1,2,4- oxadiazolyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 2nd peak 443:1H NMR (400 MHz, MeOD) 6 8.25 — 8.03 (m, 6H), 7.71 — 7.55 (m, 4H), 7.44 (d, J = 5.7 Hz, 2H), .26 (d, J = 5.6 Hz, 2H), 4.71 (d, J = 7.9 Hz, 2H), 4.46 — 4.26 (m, 4H), 3.37 (s, 1H), 2.66 (heptd, J = 7.0, 3.3 Hz, 2H), 1.69 (d, J = 7.1 Hz, 6H), 1.17 (d, J = 6.2 Hz,1H), 1.04 (d, J = 7.1 Hz, 6H), 0.88 (d, J = 6.9 Hz, 6H).
HRMS B m/z 428.1364 RT=2.77 min. 444 & 445: (S)(2-(1-(5- Separation was achieved by silica gel chromatography (4-fluoro (10 to 100% EtOAc / heptane) to give (S)(2-((R)—1- phenyl)pyridin (5-(4-fluoromethylphenyl)pyridin y|)ethy|amino)pyrimidin yl)ethylamino)pyrimidinyl)isopropyloxazolidin yl)isopropyloxazolidin- one and (2-((S)—1-(5-(4-fluoro 2-one methylphenyl)pyridinyl)ethylamino)pyrimidiny|) isopropyloxazolidinone 1st peak 444: HRMS(B) m/z 436.2126 (M + H)+, RT=2.78min 2nd peak 445:1H NMR (400 MHz, CDCI3) 6 8.75 (dd, J = 2.3, 0.9 Hz, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.78 (dd, J = 8.1, 2.4 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 7.41 — 7.27 (m, 3H), 7.12 (dd, J = 9.4, 8.4 Hz, 1H), 5.95 (d, J = 6.5 Hz, 1H , 5.16 brs, 1H ,4.66 brs, 1H ,4.34—4.19 m, WO 46136 2H), 2.37 (d, J = 1.9 Hz, 3H), 1.93 (br s, 1H), 1.65 — 1.61 (m, 3H), 0.71 (br s, 6H). HRMS(B) m/z 436.2131 446 & 447: (S)(2-(1-(5- Chiral separation was achieved by chiral SFC column (4- chromatography (Column IA mm column 30% phenoxy)pyrimidin- IPA, 70% CO2) to give (S)(2-((S)(5-(4- 2-yl)ethylamino)pyrimidin- fluorophenoxy)pyrimidinyl)ethylamino)pyrimidiny|)- 4-y|) 4-isopropyloxazolidinone and (S)(2-((R)(5-(4- pyloxazolidinone fluorophenoxy)pyrimidinyl)ethylamino)pyrimidiny|)- 4-isopropyloxazolidinone 1st peak 446: 1H NMR (400 MHz, CDCI3) 5 8.42 (s, 2H), 8.21 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 7.18 — 6.99 (m, 4H), 6.18 (br s 1H), 5.28 (br s, 1H), 4.75 (dt, J = 8.2, 3.4 Hz, 1H), 4.39 — 4.25 (m, 2H), 2.34 (br s, 1H), 1.65 — 1.59 (m, 3H), 0.95 — 0.86 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H). HRMS(B) m/z 439.1876 (M + H)+. 2nd peak 447: HRMS(B) m/z 439.1883 (M + H)+, RT = 448 & 449: (S)(2-(1-(5- Separation was achieved by silica gel chromatography (4-fluorophenoxy)pyridin- (20 to 100% EtOAc / heptane) to give (S)(2-((R)(5- 2-yl)ethylamino)pyrimidin- orophenoxy)pyridiny|)ethylamino)pyrimidinyl)- 4-y|) 4-isopropyloxazolidinone and (S)(2-((S)(5-(4- isopropyloxazolidinone fluorophenoxy)pyridinyl)ethy|amino)pyrimidinyl) isopropyloxazolidinone 1st peak 448: HRMS(B) m/z 438.1922 (M + H)+. RT = 2.62min 2nd peak 449: 1H NMR (400 MHz, CDCI3) 5 8.34 (dd, J = 2.7, 0.8 Hz, 1H), 8.21 (d, J = 5.8 Hz, 1H), 7.49 (d, J = .8 Hz, 1H), 7.33 — 7.18 (m, 3H), 7.14 — 6.95 (m, 3H), .95 (d, J = 7.1 Hz, 1H), 5.14 (br s, 1H), 4.68 (d, J = 7.8 Hz, 1H), 4.36 — 4.22 (m, 2H), 1.75 (br s, 1H), 1.61 — 1.57 (m, 3H), 0.95 - 0.75 (m, 6H). HRMS(B) m/z 438.1950 M + H +. 450 & 451: (R)(5- Separation was achieved by silica gel chromatography fluoro(1-(5-(4- (10 to 100% EtOAc / heptane) to give (R)(5-fluoro fluorophenoxy)pyridin ((S)(5-(4-f|uorophenoxy)pyridin y|)ethy|amino)pyrimidin y|)ethy|amino)pyrimidinyl)-5,5-dimethyl y|)-5,5-dimethyl phenyloxazolidinone and (R)(5-fluoro((R)(5- phenyloxazolidinone (4-fluorophenoxy)pyridiny|)ethylamino)pyrimidinyl)- ,5-dimethylphenyloxazolidinone 1st peak 450: 1H NMR (400 MHz, CDCI3) 5 8.27 — 8.17 (m, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.31 — 6.86 (m, 11H), .83 (d, J = 7.2 Hz,1H),5.28(s, 1H), 4.69 (br s,1H), 1.58 (s, 3H), 1.29 — 1.11 (m, 3H), 0.98 (s, 3H).
HRMS(B) m/z 05 (M + H)+. 2nd peak 451: HRMS(B) m/z 518.2003 (M + H)+, RT = 3.08min 452 & 453: (S)(2-(1-(5- Separation was achieved by silica gel chromatography (4-fluorophenoxy)pyrazin- (25 to 100% EtOAc / heptane) to give (S)(2-((R) 2-yl)ethylamino)pyrimidin- (5-(4-fluorophenoxy)pyraziny|)ethylamino)pyrimidin- 4-y|) 4-yl)isopropyloxazolidinone and (2-((S)(5- isopropyloxazolidinone. (4-fluorophenoxy)pyrazinyl)ethy|amino)pyrimidin y|)isopropyloxazolidinone. oeak 452: HRMS B m/z 439.1877 M + H +, RT = 2.66min 2nd peak 453: 1H NMR (400 MHz, CDCI3) 6 8.38 (d, J = 1.4 Hz, 1H), 8.20 (d, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.49 (d, J = 5.8 Hz, 1H), 7.12 (d, J = 6.3 Hz, 4H), 5.71 (s, 1H), 5.20 (br s, 1H), 4.66 (dt, J = 7.7, 2.9 Hz, 1H), 4.36 — 4.22 (m, 2H), 2.10 (br s,1H), 1.61 (d, J = 6.9 Hz, 3H), 0.94 — 0.78 (m, 6H). HRMS(B) m/z 439.1882 (M + H)+. 454 & 455: (S)(2-(1-(2- Separation was achieved by silica gel chromatography (4- (25 to 100% EtOAc / heptane) to give (S)(2-((R)—1-(2- fluorophenoxy)pyrimidin- (4-fluorophenoxy)pyrimidinyl)ethylamino)pyrimidin -yl)ethylamino)pyrimidin- y|)isopropyloxazolidinone and (S)(2-((S)—1-(2- 4-y|) (4-fluorophenoxy)pyrimidinyl)ethylamino)pyrimidin isopropyloxazolidinone. y|)isopropyloxazolidinone. 1st peak 454: HRMS(B) m/z 439.1904 (M + H)+, RT = 3.09 min 2nd peak 455: HRMS(B) m/z 439.1897 (M + H)+ RT = 3.17 min 456: (S)(2-(1-(5-(2,4- tion was ed on a normal phase silica gel difluorophenoxy)pyrimidin- column with 20 to 100% cetate / heptane to give 2-yl)ethylamino)pyrimidin- (S)(2-((R)—1-(5-(2,4-difluorophenoxy)pyrimidin 4-y|) yl)ethylamino)pyrimidinyl)isopropyloxazolidin isopropyloxazolidinone. one and (S)(2-((S)—1-(5-(2,4- rophenoxy)pyrimidinyl)ethylamino)pyrimidin y|)isopropyloxazolidinone. 2nd Peak 456: 1H NMR (400 MHz, CDCI3) 5 8.30 (s, 2H), 8.09 (d, J = 5.9 Hz, 1H), 7.42 (d, J = 5.9 Hz, 1H), 7.08 (td, J = 8.9, 5.4 Hz, 1H), 6.98 — 6.81 (m, 2H), 5.18 (br s, 1H), 4.64 (dt, J = 7.9, 3.1 Hz, 1H), 4.30 — 4.16 (m, 2H), 2.11 (br s, 1H), 1.53-1.49 (m, 3H), 0.85 — 0.77 (m, 3H), 0.71 (d, J = 6.8 Hz, 3H). HRMS(B) m/z 457.1797 (M + 457: (S)isopropyl(2- Separation was achieved on a normal phase silica gel (1 -(5-(3- column with 25 to 100% gradient of (25% methanol in (trifluoromethyl)phenyl)pyr ethylacetate) and heptane to give isopropyl(2- imidin ((R)—1-(5-(3-(trifluoromethyl)phenyl)pyrimidin y|)ethy|amino)pyrimidin yl)ethylamino)pyrimidinyl)oxazolidinone and (S) y|)oxazolidinone. isopropyl(2-((S)—1-(5-(3- (trifluoromethyl)phenyl)pyrimidin yl)ethylamino)pyrimidinyl)oxazolidinone.
Peak 2 457:1H NMR (400 MHz, CDCI3) 5 8.85 (s, 2H), 8.14 (d, J = 5.7 Hz, 1H), 7.77 — 7.54 (m, 4H), 7.40 (d, J = 5.7 Hz, 1H), 6.11 (br s, 1H), 5.25 (br s, 1H), 4.67 (dt, J = 7.8, 3.2 Hz, 1H), 4.33 — 4.15 (m, 2H), 2.92 2.15 (br s, 1H), 1.55 (d, J = 8.6 Hz, 3H), 0.85 — 0.76 (m, 3H), 0.70 br s, 3H . HRMS B m/z 473.1897 M + H +. 458: (S)(2-((S)(5-(4- The chiral separation was carried out with SFC (IA, —2- 5pm, 20 x 250 mm) using 35% MeOH in CO2 to give methylphenyl)pyrimidin (2-((S)—1-(5-(4-fluoromethylphenyl)pyrimidin y|)ethy|amino)pyrimidin yl)ethylamino)pyrimidinyl)isopropyloxazolidin yl)isopropyloxazolidin- one and (S)(2-((R)—1-(5-(4-fluoro 2-one methylphenyl)pyrimidinyl)ethylamino)pyrimidinyl)— 4-isopropyloxazolidinone 1st Peak 458: 1H NMR (400 MHz, CDCI3) 5 8.68 (s, 2H), 8.24 d, J = 5.8 Hz, 1H , 7.49 d, J = 5.7 Hz, 1H 7.17 WO 46136 (dd, J = 8.4, 5.8 Hz, 1H), 7.10 — 6.98 (m, 2H), 6.28 (br s, 1H), 5.34 (br s, 1H), 4.78 (dt, J = 8.2, 3.3 Hz, 1H), 4.40 — 4.25 (m, 2H), 2.30 (s, 3H), 1.79 (br s, 1H), 1.73 (d, J = 7.1 Hz, 3H), 0.95 — 0.75 (m, 6H). HRMS(B) m/z 437.2088 M + H +.
Example 459 N\140O HNJL /N N HO\/(>/K )_/ A solution of (S)-(4-(1-aminoethyl)phenyl)methanol hydrochloride (4.0301 g, 21.47 mmol, purchased from NetChem), (S)(2-fluoropyrimidinyl)isopropyloxazolidinone (5.3648 g, 23.82 mmol, 1.11 equiv) and DIPEA (38.0 mL, 218 mmol, 10.1 equiv) in DMSO (40 mL) was heated at 110 °C for 135 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL). After separation, the aqueous phase was washed with EtOAc (2 x 150 mL). ed organics were dried over Na2804, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 30 to 100%) provided (S)(2-((S)—1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone (6.42 g) in 84% yield. 1H NMR (400 MHz, CD30D) 8 8.13 (d, J = 5.8 Hz, 1 H), 7.36 - 7.28 (m, 5 H), 5.06 (q, J = 7.0 Hz, 1 H), 4.68 (br s, 1 H), 4.58 (s, 2 H), 4.37 - 4.29 (m, 2 H), 1.80 (br s, 1 H), 1.52 (d, J = 7.1 Hz, 3 H), 0.74 (br s, 3 H), 0.61 (br s, 3 H); MS m/z 355.1 (M - H) Example 460 HNAN/ Nioo F )_/ HO \\ S)—3-(2-((S)—1-(3-f|uoro(hydroxymethyl)phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone was ed using a method similar to that described for the preparation of Example 459.1H NMR (400 MHz, CDCI3) 8 8.15 (d, J = 5.9 Hz, 1 H), 7.51 - 7.49 (m, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.11 (d, J = 7.8 Hz, 1 H), 7.01 (d, J =11, Hz, 1 H), 6.09 (br s, 1 H), 5.00 (br s, 1 H), 4.73 (s, 2 H), 4.61 - 4.55 (m, 1 H), 4.30 (t, J = 8.7 Hz, 1 H), 4.25 - 4.21 (m, 1 H), 3.00 (s, 1 H), 1.89 (br s, 1 H), 1.54 (d, J = 7.1 Hz, 3 H), 0.67 (br s, 6 H); MS m/z 375.0 (M + H) Example 461 A solution of (2-chloropyrimidinyl)isopropyloxazolidinone (50mg, 0.165mmol), 2,2,2-trifluorophenylethanamine (160mg, 0.913mmol) and stOH (78mg, 0.412mmol)in 2-BuOH was heated at 110°C for 2.5h. LCMS shows starting material as well as product. Another 78mg of stOH was added followed by 98mg of trifluoro- 1-phenylethanamine and heated at 110C for 1.5h. Mostly product some SM.
After cooling down mixture fied. Added acetonitrial and sonicated. Filtered off solids (stOH salt of 2,2,2-trifluorophenylethanamine). The mother liquor was concentrated and purified by column chromatography (0-40% EtOAc/Hept followed by reverse HPLC (XBridge C18 5uM 10-85% ACN/Water over 12 minutes with 0.01%NH4OH er) to give (4R)—5,5-dimethylphenyl(2-(2,2,2-trifluorophenylethylamino)pyrimidin y|)oxazolidinone (28mg, 0.063mmol). 1H NMR (400 MHz, MeOD) 5 8.20 (d, J = 5.8 Hz, 1H), 7.58 (dd, J = 11.4, 5.8 Hz, 1H), 7.51 (br d, J = 6.8 Hz, 1H), 7.40 (dtd, J = 15.9, 9.2, 4.5 Hz, 5H), 7.33 — 7.22 (m, 3H), 7.10 (br s, 1H), 5.50 (s, 0.5H), 5.38 (s, 0.5H), 5.29 (br s, 1 H), 1.70 (s, 1.5H), 1.64 (s, 1.5H), 1.04 (s, 1.5H), 1.03 (s, 1.5H). HRMS(B) (M+H) 443.1682 Calc’d (M+H) 443.1695 Example 462 & 463 m0 HNAN/ NJLO CF3 \R‘ A solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (163 mg, 0.674 mmol), 2,2,2-trifluorophenylethanamine (624 mg, 3.56 mmol, 5.3 equiv) and p- toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110 °C for 2 h and treated with additional p-toluenesulfonic acid drate (321 mg, 1.69 mmol, 2.5 equiv), then heated at 110 °C for 1 1/2 h. After cooling, the solid reaction mixture was treated with MeCN, sonicated and filtered. The filtrated was concentrated and purified by silica gel column chromatography (EtOAc/Heptane 0 to %) to give (4S)—4-isopropyl(2-(2,2,2-trifluorophenylethylamino)pyrimidin yl)oxazolidinone (65 mg) in 25% yield. HRMS(B) m/z 381.1545 (M + H)+. Anal. RP- HPLC tR = 4.31//4.46 min (1.0 mL/min flow rate with gradient from 5% to 15% acetonitrile with 0.05% formic acid in 5.00 min and then 15% to 95% acetonitrile with 0.05% formic acid from 5.00 min to 9.50 min, aqueous phase modified with 0.1% formic acid. Silica gel column chromatography ted the two diastereomers (S)isopropyl- 3-(2-((R)—2,2,2-trifluorophenylethylamino)pyrimidinyl)oxazolidinone and (S)—4- pyl(2-((S)-2,2,2-trifluorophenylethylamino)pyrimidinyl)oxazolidinone. 1St Peak : 1H NMR (400 MHz, MeOD) 5 8.23 (d, J = 5.8 Hz, 1H), 7.62 — 7.53 (m, 2H), 7.50 (d, J = 5.8 Hz, 1H), 7.42 (qt, J = 5.0, 2.2 Hz, 3H), 5.93 — 5.86 (m, 1H), 4.80 (dt, J = 7.5, 3.9 Hz, 1H), 4.48 — 4.33 (m, 2H), 2.65 (ddp, J = 10.4, 7.0, 3.4 Hz, 1H), 1.05 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H). 2nd Peak: 1H NMR (400 MHz, MeOD) 5 8.23 (d, J = 5.8 Hz, 1H), 7.55 (dd, J = 7.3, 2.1 Hz, 2H), 7.49 (d, J = 5.8 Hz, 1H), 7.45 — 7.32 (m, 3H), 5.92 — 5.86 (m, 1H), 4.86 — 4.82 (m, 1H), 4.44 — 4.38 (m, 2H), 2.26 (br s, 1H), 0.94 (d, J = 7.0 Hz, 3H), 0.74 (br s, 3H).
Example 464 JCL JLN \ o HN N N O l ”Y‘“ a\ A solution of (S)—3-(2-fluoropyrimidinyl)isopropyloxazolidinone (1055 mg, 4.68 mmol), 1-(5-(4-f|uoromethylphenyl)pyrimidinyl)ethanamine (1300 mg, 5.62 mmol, 1.2 equiv) and diisopropylethylamine (908mg, 7.03mmol, 1.5 equiv) in DMSO (20 mL) was heated at 110 °C for 1 h. The reaction mixture was poured into water (60 mL) and ted with EtOAc (2x50 mL). Combined cs were washed with water (40mL), brine (40mL), dried over Na2804, filtered and concentrated directly onto silica gel. Silica gel chromatography provided the mixed distereomers of (S)(2-(1-(5-(4-fluoro methylphenyl)pyrimidinyl)ethylamino) pyrimidinyl)isopropyloxazolidinone (560mg). Chiral separation was carried out with SFC (ID, 5pm, 20 x 250 mm) using 35% MeOH in C02 to give (S)—3-(2-((S)—1-(5-(4-f|uoromethylphenyl)pyrimidin yl)ethylamino)pyrimidinyl)isopropyloxazolidinone and (S)(2-((R)—1-(5-(4-fluoro- ylphenyl)pyrimidinyl)ethylamino)pyrimidinyl)isopropyloxazolidinone.
Example 464 first eluted product (302 mg) 1H NMR (400 MHz, CDCI3) 6 8.87 (s, 2H), 8.23 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 7.43 — 7.30 (m, 2H), 7.21 — 7.11 (m, 1H), 6.26 (br s, 1H), 5.31 (br s, 1H), 4.75 (dt, J = 7.9, 3.3 Hz, 1H), 4.39 — 4.24 (m, 2H), 2.38 (s, 3H), 2.09 (br s, 1H), 1.66-1.62 (m, 3H), 0.90 (dd, J = 9.8, 6.0 Hz, 3H), 0.78 (br s, 3H). HRMS(B) m/z 437.2093 (M + H)+.
Example465 HNAN/ NAG“Ii F L/ (EL ,N \\ o” *0 A solution of (S)isopropyl(2-((S)(piperidinyl)ethylamino)pyrimidin yl)oxazolidinone (225mg, 0.675mmol), 4-fluorobenzenesulfonyl chloride , 0.750mmol) and DIPEA (1ml) in CH2C|2 was stirred at room temperature for 2h.
The reaction mixture was d with CH2C|2 and washed with water. Aqueous layer was extracted with CH2C|2. Combined organics were washed with brine, dried over Na2804, filtered and concentrated. The e was purified by column chromatography to give (S)(2-((S)—1-(1-(4-f|uorophenylsulfonyl)piperidinyl)ethylamino)pyrimidiny|)- 4-isopropyloxazolidinone (4.5mg, 0.009mmol). 1H NMR (400 MHz, MeOD) 6 8.45 (d, J = 6.0 Hz, 1H), 8.23 — 8.15 (m, 2H), 7.73 — 7.63 (m, 3H), 5.13 (dt, J = 7.4, 3.7 Hz, 1H), 4.78 — 4.69 (m, 2H), 4.26 (p, J = 6.7 Hz, 1H), 4.17 (dddd, J = 11.8, 6.4, 4.7, 2.3 Hz, 2H), 2.89 (ddq, J = 10.7, 7.1, 3.5 Hz, 1H), 2.69 (tdd, J = 11.6, 8.9, 2.6 Hz, 2H), 2.27 — 2.11 (m, 2H), 1.82 (dddt, J = 11.9, 9.0, 5.8, 2.9 Hz, 1H), 1.77 — 1.64 (m, 2H), 1.52 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 492.2069 Calc’d (M+H) 492.2081 The following examples were ed using methods substantially similar to those described for Example 465: 2012/055133 Example466 “Ii 0 HNAN/ NJLO (gm 5“” Purified by column chromatography (20% to 100% EtOAc/Hept), followed by reverse phase preparative chromatography (C18 column, 10-85% ACN/Water 0.1% NH4OH er over 12 min.) to give (S)—3-(2-((S)—1-(1-(4-f|uorobenzoyl)piperidin yl)ethylamino)pyrimidinyl)isopropyloxazolidinone (12mg, 0.026mmol). 1H NMR (400 MHz, MeOD) 5 8.12 (d, J = 5.8 Hz, 1H), 7.51 — 7.41 (m, 2H), 7.36 (d, J = .8 Hz, 1H), 7.25 — 7.15 (m, 2H), 4.82 (td, J = 5.9, 3.6 Hz, 1H), 4.68 (br s, 1H), 4.41 (d, J = 5.7 Hz, 2H), 3.98 (p, J = 6.7 Hz, 1H), 3.78 (br s, 1H), 3.12 (br s, 1H), 2.82 (br s, 1H), 2.60 (pd, J = 7.1, 6.5, 3.7 Hz, 1H), 1.92 (br s, 1H), 1.80 (dtd, J = 15.3, 9.4, 7.0, 3.6 Hz, 2H), 1.31 (br s, 2H), 1.22 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 456.2384 Calc’d (M+H) 456.2411 Example467 HNAN/“IiNJKO mm a” Purified by column chromatography (MeOH/CH2C|2 0 to 20%) to give (S)—4-isopropyl (2-((S)(1-(tetrahydro-2H-pyrancarbonyl)piperidinyl)ethylamino)pyrimidin yl)oxazolidinone (15mg, mol). 1H NMR (400 MHz, MeOD) 6 8.12 (d, J = 5.8 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 4.81 (td, J = 5.6, 3.3 Hz, 1H), 4.59 (br s, 1H), 4.41 (d, J = 5.7 Hz, 2H), 4.13 (br s, 1H), 3.96 (ddd, J = 11.6, 4.3, 2.2 Hz, 3H), 3.51 (tq, J = 11.8, 2.8 Hz, 2H), 3.15 — 2.89 (m, 2H), 2.69 — 2.48 (m, 2H), 1.99 — 1.68 (m, 5H), 1.61 (ddt, J = 10.7, 4.0, 2.3 Hz, 2H), 1.35 — 1.23 (m, 1H), 1.21 (d, J = 6.7 Hz, 3H), 1.19 — 1.09 (m, 1H), 0.98 (dd, J = 7.0, 1.5 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H). HRMS(B) (M+H) 446.2748 Calc’d (M+H) 446.2767 2012/055133 Example468 HNAN/”IiNJLO 0040* a” Purified by column chromatography (50% to 100% EtOAc/Heptane follwed by 0% to 20% MeOH/CHzClz) to give (S)isopropy|—3-(2-((S)—1-(1-(morpho|inecarbonyl)piperidin y|)ethy|amino)pyrimidiny|)oxazo|idinone (21mg, 0.047mmol). 1H NMR (400 MHz, MeOD) 5 8.11 (d, J = 5.8 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 4.81 (td, J = 5.8, 3.4 Hz, 1H), 4.41 (d, J = 5.7 Hz, 2H), 3.95 (p, J = 6.8 Hz, 1H), 3.84 — 3.70 (m, 2H), 3.68 — 3.65 (m, 4H), 3.26 — 3.23 (m, 4H), 2.80 (tt, J = 12.9, 3.1 Hz, 2H), 2.60 (ddq, J = .4, 7.0, 3.5 Hz, 1H), 1.88 — 1.73 (m, 2H), 1.67 (ddt, J = 18.5, 10.4, 3.5 Hz, 1H), 1.37 — 1.23 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H).
HRMS(B) (M+H) 447.2690 Calc’d (M+H) 447.2720 Example469 ”Ii 0 HNAN/ NAG 040* a” Purified by column tography to give (S)(2-((S)—1-(1-(cyc|ohexanecarbony|) piperidinyl)ethylamino)pyrimidinyl)isopropy|oxazo|idinone 1H NMR (400 MHz, MeOD) 5 8.12 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 5.6 Hz, 1H), 4.80 (dt, J = 5.8, 2.9 Hz, 1H), 4.59 (br s, 1H), 4.40 (d, J = 5.6 Hz, 2H), 4.18 — 4.03 (m, 1H), 3.95 (p, J = 6.8 Hz, 1H), 3.05 (ddd, J = 14.1, 10.1, 6.6 Hz, 1H), 2.58 (td, J = 25.1, 23.5, 13.0 Hz, 3H), 1.97 — 1.63 (m, 8H), 1.54 — 1.08 (m, 7H), 1.21 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H). HRMS(B) (M+H) 444.2953 Calc’d (M+H) 444.2975 Examples 470 HNDJ:N N Oslo/GA L/° \\\\\~\‘ //\N O I A solution of (S)(2-(((S)—1-(4-aminophenyl)ethyl)amino)pyrimidiny|) isopropyloxazolidinone (100 mg, 0.30 mmol), benzenesulfonyl chloride (65 mg, 0.36 mmol, 1.2 equiv) and ne (35 mg, 0.45 mmol, 1.5 equiv) in DCM (5 mL) was stirred at room temperature for 15 h. The reaction e was quenched with MeOH, the solvent was removed to yield the crude product, which was purified by silica gel column chromatography (EA:MeOH=1:0 to 9:1), the solvent was removed to afford the pure product (46.8mg, white solid ) in a 31.5% yield. N-(4-((S)((4-((S)isopropyl oxooxazolidinyl)pyrimidinyl)amino)ethy|)phenyl)benzenesulfonamide. 1H NMR (400 MHz, CDCI3) 5 8.18 — 7.90 (m, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.39 — 7.35 (m, 2H), 7.10 (d, J = 8.1 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.41 (s, 1H), 4.99 — 4.79 (m, 1H), 4.62 — 4.39 (m, 1H), 4.28 — 3.99 (m, 2H), 1.91 — 1.65 (b, 1H), 1.40 (d, J = 7.0 Hz, 3H), 0.53 (b, J = 21.1 Hz, 6H). HRMS(B) m/z 482.1847 (M + H)+. RT=2.60 min.
Examples 471 1.11 NINYK \\‘“\\/o \ o \\ A solution of (triethoxymethyl)benzene (360 mg, 1.6 mmol, 5.0 equiv. in 5 mL of benzene and 0.5 mL of glacial AcOH) was added to (S)((4-((S)isopropy| oxooxazolidinyl)pyrimidinyl)amino)propanehydrazide (99 mg, 0.30 mmol, 1.0 equiv.), the reaction mixture was d at reflux for 1.5 hours, the solvent was d to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 90%) to yield (S)isopropy|(2-(((S)(5-pheny|-1,3,4-oxadiazo| yl)ethyl)amino)pyrimidinyl)oxazolidinone (21.2 mg, white solid) in 15.9% yield.
HRMS(B) m/z 395.1820, (M+H )+, RT=2.42 min Examples 472 agoo O\\S /S\\O To a solution of (S)isopropy|(2-(((S)(5-(methy|thio)-1,3,4-oxadiazolyl)ethy|) pyrimidinyl)oxazolidinone (102 mg, 0.28 mmol in 1.5 ml of CH3COOH ), was added a solution of KMnO4 (66.4 mg, 0.42 mmol, 1.5 eq in 2.5 ml of water) dropwise.
The on was stirred at room temperature for 25 min, the mixture was decolorized with sodium bisulfite, the resulting solution was extracted with DCM, washed with sat.
NaHCO3, dried over Na2804, the solvent was removed to yield the pure desired product as a white solid. (S)isopropyl(2-(((S)—1-(5-(methylsulfonyl)-1,3,4-oxadiazol yl)ethyl)amino)pyrimidinyl)oxazolidinone (83 mg, white solid) in 71 % yield.
HRMS(B) m/z 397.1281 (M + H)+. RT=1.80 min. e 473 & 474 N\ o NNJLN NJko W \i“ 1-(1H-Pyrrolo[2,3-b]pyridinyl)—ethanone (75 mg, 0.468 mmol), ammonium acetate (722 mg, 9.36 mmol, 20.0 eq) and sodium cyanoborodeuteride (131 mg, 1.999 mmol, 4.25 eq) were combined in propanol (5 ml) and heated under infrared irradiation at 130°C for 4 min. The reaction was diluted with EtOAc (15 ml) and water (15 ml) and treated with 6M NaOH solution (1 ml) to ~10 pH. The product, 1-deutero(1H-pyrrolo[2,3-b]pyridin yl)ethanamine, was carried to the next step without further purification.
A solution of 3-(2-fluoropyrimidinyl)oxazolidinone (99 mg, 0.441 mmol), 1-deutero— pyrrolo[2,3-b]pyridinyl)ethanamine ( 72 mg, 0.441 mmol, 1.0 equiv), and DIEA (0.154 mL, 0.882 mmol, 2.0 equiv) in DMSO (1 mL) was heated at 130 °C for 120 min.
The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) 2012/055133 and concentrated in vacuo. Resolution of (4S)—3-(2-((1-deutero(1H-pyrrolo[2,3- b]pyridinyl)ethyl)amino)pyrimidinyl)isopropyloxazolidinone via chiral SFC chromatography on a Al column (75 g/min, 120 bar, 20 x 250 mm) eluting 40-50% MeOH/0.2% DEA/CO2 (v/v) to give (4S)—3-(2-(((R)—1-deutero(1H-pyrrolo[2,3-b]pyridin- -yl)ethyl)amino)pyrimidinyl)isopropyloxazolidinone and (4S)—3-(2-(((S)—1- deutero(1H-pyrrolo[2,3-b]pyridinyl)ethyl)amino)pyrimidinyl) isopropyloxazolidinone 1st peak 473 1H NMR (400 MHz, CDCI3)610.10(s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 5.7 Hz, 1H), 7.35 (dd, J = 3.5, 2.0 Hz, 1H), 6.47 (dd, J = 3.4, 1.7 Hz, 1H), 5.82 (s, 1H), 1.66 — 1.58 (m, 3H), 4.59 (dt, J = 7.7, 3.2 Hz, 1H), 4.28 (t, J = 8.8 Hz, 1H), 4.19 (dd, J = 9.2, 3.1 Hz, 1H), 3.51 (s, 1H), 1.78 (d, J = 28.5 Hz, 2H), 1.30 — 1.15 (m, 1H), 0.57 (s, 6H). LCMS m/z 368.1 (M+H) RT=2.36 min. 2nd peak 474 LCMS m/z 368.1 (M+H) RT=2.66 min.
Example 475 NAN/“Ii N’0 H NJLO I N/>~/ )_/ A solution of 3-(2-fluoropyrimidinyl)oxazolidinone (100 mg, 0.444 mmol), (3-(p- —1,2,4-oxadiazolyl)methanamine ( 84 mg, 0.444 mmol, 1.0 equiv), and TEA (0.186 mL, 1.332 mmol, 3.0 equiv) in butanol (2 mL) was heated at 100 °C for 90 min. Addition of propanol (1 ml) and heated at 150 °C for 60 min. The reaction mixture was concentrated in vacuo. Flash column (silica, 24 g) eluting w/ 0 - 30% EtOAc/DCM afforded (S)lsopropyl{2-[(3-p-tolyl-[1,2,4]oxadiazolylmethyl)—amino]- pyrimidinyl}-oxazolidinone (95 mg, white foam) in 54.2% yield. HRMS(B) m/z 394.1753 2.38 Min.
Example 476 To a solution of 4-{(S)—1-[4-((S)—4-|sopropyIoxo-oxazolidiny|)-pyrimidinylamino]- ethyl}-piperidine—1-carboxy|ic acid benzyl ester (22 mg) in methanol (5 mL) was added palladium hydroxide on carbon (7 mg, 0.05 mmol). The reaction was then stirred at room temperature for 16 hours. The on is then filtered and then concentrated under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)isopropyI[2-((S)piperidiny|— ethylamino)—pyrimidiny|]-oxazo|idinone (11 mg) in 70% yield. ) m/z 333.2165 (M + H)+; RT.: 1.09 min. e 477 >/'Z\.3>=o A solution of |sopropyI[2-((S)piperidiny|—ethy|amino)—pyrimidiny|]- oxazolidinone (28 mg, 0.084 mmol) in THF (2 mL) was added cyclobutanone (14 mg, 0.20 mmol) and sodium triacetoxyborohydride (28 mg, 0.13 mmol). The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum.
The crude material was then purified using reverse phase C18 ODB column water- acetonitrile 0.1% TFA modifier to give (S){2-[(S)—1-(1-Cyc|obuty|-piperidiny|)- ethylamino]—pyrimidiny|}isopropyI-oxazolidinone (20 mg) in 62% yield.
HRMS(B) m/z 388.2717 (M + H)+; RT.: 2.32 min.
Example 478 @1010N: O 7 a A on of (S)—4-lsopropyl[2-((S)—1-piperidinyl-ethylamino)—pyrimidinyl]- oxazolidinone (20 mg, 0.060 mmol) in THF (2 mL) was added cyclobutanone (10 mg, 0.17 mmol) and sodium triacetoxyborohydride (20 mg, 0.09 mmol). The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum.
The crude material was then purified using reverse phase C18 ODB column water- acetonitrile 0.1% TFA modifier to give lsopropyl{2-[(S)—1-(1-isopropyl-piperidin yl)—ethylamino]-pyrimidinyl}-oxazolidinone (20 mg) in 62% yield. ) m/z 376.2705 (M + H)+; RT.: 1.24 min.
Example 479 N/ OAHNAN“t N/lko 0 \ To a solution of S)—4-lsopropyl[2-((S)—1-piperidinyl-ethylamino)—pyrimidinyl]- oxazolidinone (20 mg, 0.48 mmol) in dichloromethane (1 mL) and DMF (1 mL) was added HATU (23 mg, 0.06 mmol) and DIPEA (0.03 mL, 0.18 mmol) The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum.
The crude material was then purified using reverse phase C18 ODB column water- acetonitrile 0.1% TFA modifier to give (S)lsopropyl(2-{(S)—1-[1-(pyridine carbonyl)—piperidinyl]-ethylamino}-pyrimidinyl)-oxazolidinone (2 mg) in 8% yield.
HRMS(B) m/z 438.2379 (M + H)+; RT.: 1.82 min.
Example 480 /N OANflN/lio To a on of S)—4-lsopropyl[2-((S)—1-piperidinyl-ethylamino)—pyrimidinyl]- oxazolidinone (16 mg, 0.48 mmol) in romethane (1 mL) and DMF (1 mL) was added HATU (20 mg, 0.05 mmol) and DiPEA (0.03 mL, 0.15 mmol) The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum.
The crude material was then purified using reverse phase C18 ODB column water- acetonitrile 0.1% TFA er to give (S)lsopropyl(2-{(S)—1-[1-(pyridine carbonyl)—piperidinyl]-ethylamino}-pyrimidinyl)—oxazolidinone (2 mg) in 8% yield. ) m/z 438.2379 (M + H)+; RT.: 1.83 min.
Example 481 & 482 //N N Nl H UN _\ To a solution of (S)lsopropyl[2-((S)—1-methyl-propynylamino)—pyrimidinyl]— oxazolidinone (60 mg, 0.22 mmol) and benzyl azide (30 mg, 0.23 mmol) in water (0.5 mL) and DMSO (3 mL) was added copper sulfate pentahydrate (56 mg, 0.23 mmol) and L-ascorbic acid sodium salt (45 mg, 0.23 mmol). The reaction was stirred for 48 hours at room temperature. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (15 mL) and 1N solution sodium bicarbonate (15 mL) . The organic layer was dried over MgSO4, filtered and concentrated. The crude material was then purified on reverse phase using a C18 n water-acetonitrile TFA as a modifier, which also ed separation of the two diastereomer products (S){2-[(S)—1-(1-benzyl-1H- [1,2,3]triazolyl)-ethylamino]-pyrimidiny|}isopropyl-oxazolidinone and {2- [(R)—1-(1-benzyl-1H-[1,2,3]triazolyl)-ethylamino]-pyrimidiny|}isopropyl-oxazolidin- 2-one First Peak 481: HRMS(B) m/Z 407.2070 (M + H)+; RT.: 2.26 min.
Second Peak 482: HRMS(B) m/Z 407.2070 (M + H)+; RT.: 2.32 min.
Example 483 & 484 N/ 0 Ni’ l H .u N .
To a solution of (S)lsopropyl[2-((S)—1-methyl-propynylamino)—pyrimidinyl]— oxazolidinone (82 mg, 0.30 mmol) and azidobenzene (36 mg, 0.30 mmol) in water (0.5 mL) and DMSO (3 mL) was added copper sulfate pentahydrate (75 mg, 0.23 mmol) and L-ascorbic acid sodium salt (60 mg, 0.23 mmol). The reaction was stirred for 48 hours at room temperature. The reaction e was d with EtOAc (75 mL) and washed with water (15 mL) and 1N solution sodium bicarbonate (15 mL) . The c layer was dried over MgSO4, filtered and concentrated. The crude material was then purified on reverse phase using a C18 columnn water-acetonitrile TFA as a modifier , which also effected separation of the two diastereomer products (S)isopropyl{2- [(S)(1-phenyl-1H-[1,2,3]triazolyl)-ethylamino]-pyrimidinyl}-oxazolidinone and (S)—4-isopropyl{2-[(R)—1-(1-phenyl-1H-[1,2,3]triazolyl)-ethylamino]-pyrimidinyl}- oxazolidinone First Peak 483: HRMS(B) m/z 393.1913 (M + H)+; RT.: 2.31 min.
Second Peak 484: HRMS(B) m/z 393.1913 (M + H)+; RT.: 2.40 min.
Example 485 N N gIIII / TI CY0% To a room ature solution of 3-(2-chloro—5-fluoropyrimidinyl)—5,5- dimethyloxazolidinone (30 mg, 0.122 mmol) in DMSO (300 uL) was treated with DIPEA (68 uL, 0.366 mmol) followed by on of (S)(2-fluoro—4- (trifluoromethyl)phenyl)ethanamine (41.4 mg, 0.2 mmol). The reaction was sealed, heated at 95°C for ~18 hr. . Purification by reverse phase HPLC provided the trifluoroacetate salt of (S)(5-fluoro(1-(2-fluoro(trifluoromethyl) phenyl) ethylamino)pyrimidinyl)—5,5-dimethyloxazolidinone. (6.0 mg, white solid). 1H NMR (400 MHz, METHANOL-d4) 8 ppm 1.44 - 1.58 (m, 12 H) 3.50 - 3.74 (m, 1 H) 3.88 (d, J=9.8 Hz 1 H) 5.29 (d, J=7.04 Hz, 1 H) 7.38 - 7.45 (m, 2 H) 7.6 (t, J=8.22 Hz 1 H) 8.16 (d, J=3.13 Hz, 1 H); HRMS(A) m/z 417.1360 (M + H)+, Rt 2.29 min.
The compounds in Table 11 were prepared using methods similar to those described for the preparation of Example 485.
WO 46136 Table 11.
WO 46136 Table 12. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 11. —__—— 486: 3-(5-fluoro((S)—1- (CD30D) 1.41 - 1.58 (m, 8 H) 3.55 (br. 3., 1 HRMS(A) (2-fluoro H) 3.74 - 3.80 (m, 1 H) 4.17 (dd, J=9.59, m/z (trifluoromethyl)phenyl)eth 7.63 Hz, 1 H) 5.26 - 5.33 (m, 1 H) 7.39 - 403.1198 ylamino)pyrimidinyl) 7.45 (m, 2 H) 7.60 (t, J=7.83 Hz, 1 H) 8.15 (M + H)+, methyloxazolidinone (d, J=3.52 Hz, 1 H) Rt 2.20 487: (5-fluoro(1- (CD30D) 0.90 (m, 2 H) 1.18 - 1.27 (m, 2 H) HRMS(A) (2-fluoro 1.53 (d, J=7.04 Hz, 3 H) 4.21 (d, J=9.39 m/z (trifluoromethyl)phenyl)eth Hz, 1 H) 5.30 (d, J=7.04 Hz, 1 H) 7.38 - 415.1204 ylamino)pyrimidinyl) 7.45 (m, 2 H) 7.60 (t, J=7.83 Hz 1 H) 8.17 (M + H)+, oxa (d, J=3.52 Hz, 1 H) Rt 2.31 aza30iro 2.4 he tanone min 488: (S)(2-(1-(5-chloro- (CD30D) 8.22 (d, J=3.13 Hz, 1 H) 8.08 (d, ) 6-(2,2,2- J=1.96 Hz, 1 H) 7.84 (d, J=1.96 Hz, 1 H) m/z trifluoroethoxy)pyridin 5.26 - 5.27 (m, 1 H) 4.90 (q, 464.1125 yl)ethylamino) J=8.61 Hz, 3 H) 4.13 - 4.22 (m, 2 H) 1.47 - (M + H)+, fluoropyrimidinyl)—4,4- 1.59 (m, 9 H) Rt 2.28 dimeth loxazolidinone min 489: (S)(2-(1-(5-chloro- (CD30D) 8.51 (d, J=1.57 Hz, 1 H) 8.23 (d, HRMS(A) 6-(1,1- J=2.35 Hz, 1 H) 7.93 (d, J=1.56 Hz, 1 H) m/z difluoroethyl)pyridin 4.99 (q, J=6.52 Hz, 1 H) 2.02 (t, 458.1573 ylamino) J=18.78 Hz, 3 H) 1.57 (d, J=7.43 Hz, 3 H) (M + H)+, fluoropyrimidinyl)— 1.34 - 1.42 (m, 12 H) Rt 2.02 4,4,5,5- min tetramethyloxazolidin 490: (S)(2-(1-(5-chloro- (CD30D) 8.50 (d, J=1.17 Hz, 1 H) 8.24 (d, HRMS(A) 6-(1,1- J=2.35 Hz, 1 H) 7.93 (d, J=1.57 Hz, 1 H) m/z difluoroethyl)pyridin 4.99 (q, J=6.65 Hz, 1 H) 4.12 - 430.1265 ylamino) 4.21 (m, 2 H) 2.01 (t, J=18.78 Hz, 3 H) (M + H)+, pyrimidinyl)—4,4- 1.57 (d, J=7.04 Hz, 3 H) 1.47 (3, 6 H) Rt 2.05 dimeth loxazolidinone min 491: (S)(2-(1-(3-(4- (CD30D) 8.27 (br. 3., 1 H) 8.00 (d, J=8.61 ) chlorophenyl)—1,2,4- Hz, 3 H) 7.52 (d, J=8.61 Hz, 4 H) 5.29 (d, m/z oxadiazol J=7.04 Hz, 1 H) 1.73 (3, 3 H) 1.44 (3, 3 H) 461.1512 yl)ethylamino) 1.38 (3, 3 H) 1.28 (3, 3 H) (M + H)? fluoropyrimidinyl)— Rt2.37 4,4,5,5- min tetramethyloxazolidin 492: 3-(2-((S)(3-(4- (CD30D) 8.27 (d, J=1.57 Hz, 1 H) 8.00 (d, HRMS(A) chlorophenyl)—1,2,4- J=8.61 Hz, 2 H) 7.52 (d, J=8.61 Hz, 2 H) m/z oxadiazol 5.29 (m, 1 H) 4.44(m, 1 H) 1.73 (d, J=7.43 477.1349 yl)ethylamino) Hz, 3 H) 1.44 (br. 3., 3 H) 1.26 - 1.35 (m, 6 (M + H)+, fluoropyrimidinyl)—4,4,5- H) Rt 2.3 min trimethyloxazolidinone (1:1 mixture of diastereomers 493: (S)(2-(1-(3-(4- (CD30D) 8.28 (d, J=2.35 Hz, 1 H) 8.00 (d, HRMS(A) chlorophen |-1,2,4- J=8.61 Hz, 2 H 7.51 d, J=8.61 Hz, 2 H m/z oxadiazoI 5.29 (m, 1 H) 4.11 -4.24 (m, 2 H) 1.73 (d, 01 y|)ethy|amino)—5- J=7.04 Hz, 3 H) 1.53 (s, 3 H) 1.30 (br.s., 3 (M+Hfi fluoropyrimidiny|)-4,4- W Rt 2.21 dimeth onazolidinone min 494: (4S)—4-isopropy|—5- (CD30D) 8.11 (d, J=6.26 Hz, 1 H) 7.71 (d, HRMS(A) methyl(2-((S)—1- J=7.43 Hz, 1 H) 7.29 - 7.40 (m, 4 H) 7.22 - m/z phenylethylamino)pyrimidi 7.28 (m, 1 H) 5.23 (br. s., 1 H) 341.1985 nyl)oxazolidinone 4.82 -4.91 (m, 1 H)4.78 (br. s., 1 H)2.01 (M+Hfi (1:1 mixture of (br. s., 1 H) 1.59 (d, J=7.04 Hz, 3 H) 1.54 Rt 1.78 diastereomers) (d, J=6.65 Hz, 3 H) 0.78 (br. s., 6 H) min 495: (4S)—3-(5-f|uoro—2- (CD30D) 7.87 (d, J=3.13 Hz, 1 H) 6.95 - HRMS(A) ($7? 7.02 (m, 2 H) 8.91 (t, J=7.63 Hz, 2 H) 6.75 m/z phenylethylamino)pyrimidi - 6.85 (m, 1 H) 4.52 - 4.61 (m, 2H) 4.00 (br. 359.1891 ny|)isopropy| s., 1 H) 1.49 (br. s., 1 H) 1.11 (dd, J=9.59, (M+Hfi methyloxazolidinone 8.85 Hz, 8 H) 0.38 (d, J=4.30 Hz, 8 H) Rt 2.19 (1:1 mixture of min diastereomers 496: (S)-4,4,5,5- (CD30D) 8.08 (d, J=6.26 Hz, 1 H) 7.28 - HRMS(A) tetramethyI(2-(1- 7.40 (m, 5 H) 7.18 - 7.25 (m, 1 H) 5.05 (q, m/z phenylethylamino)pyrimidi J=7.04 Hz, 1 H) 1.55 - 1.82 (m, 8H) 1.37 84 nyl)oxazolidinone (s, 3 H) 1.32 (s, 3 H) (M+Hfi Rt 1.73 497: (S)(5-f|uoro—2-(1 - ) 8.18 (d, J=2.74 Hz, 1 H) 7.30 - HRMS(A) phenylethylamino)pyrimidi 7.39 (m, 2 H) 7.23 - 7.30 (m, 2 H) 7.12 - m/z ny|)-4,4,5,5- 7.21 (m, 1 H)4.90 (q, J=6.91 Hz, 1H) 1.50 359.1891 tetramethyloxazolidin (d, J=7.04 Hz, 3 H) 1.42 (s, 3 H) 1.38 (s, 3 (M+Hfi one H) 1.33 (s, 3 H) Rt 2.16 498: trimethyI(2- (CD30D) 8.09 (d, J=6.65 Hz, 1 H) 7.53 (d, HRMS(A) ($7? J=7.04 Hz, 1 H) 7.45 (d, J=7.04 Hz, 1 H) m/z phenylethylamino)pyrimidi 7.30 - 7.40 (m, 8 H) 7.20 - 7.28(m, 2 H) 327.1826 nyl)oxazolidinone 5.09 (t, J=7.04 Hz, 2 H) 4.27 - 4.42 (m, 2 (M+Hfi (1 :1 e of H) 1.52- 1.89 (m, 12 H) 1.32 (dd, J=11.15, Rt 1.66 reomers) 8.48 Hz, 8 H) 0.82 - 1.20 (m, 8 H) min 499: 3-(5-fluoro((S)—1- (CD30D) 8.18 (d, J=2.74 Hz, 1 H) 7.30 - HRMS(A) phenylethylamino)pyrimidi 7.37 (m, 2 H) 7.24 - 7.30 (m, 2 H) 7.11 - m/z ny|)-4,4,5- 7.21 (m, 1 H)4.87 -4.97 (m, 1 H)4.31- 345.1735 trimethyloxazolidinone 4.48 (m, 1 H) 1.50 (d, J=7.04 Hz, 3 H) 1.41 (M+Hfi (1 :1 mixture of (d, J=10.96 Hz, 3 H) 1.29 (dd, J=6.46, 3.33 Rt 2.09 diastereomers) Hz, 3 H) 0.84 - 1.18 (br. s, 3 H) min 500: (5-f|uoro—2-(1 - (CD30D) 8.19 (d, J=2.35 Hz, 1 H) 7.30 - HRMS(A) phenylethylamino)pyrimidi 7.37 (m, 2 H) 7.24 - 7.30 (m, 2 H) 7.13 - m/z ny|)-4,4- 7.21 (m, 1 H)4.91 (q, J=7.30 Hz,1H)4.12 331.1573 dimethyloxazolidinone (q, J=8.22 Hz, 2 H) 1.45 - 1.55 (m, 8 H) (M+Hfi 1.08 (br. s., 3 H) Rt 1.98 501: (4S)—3-(2-((S)—1-(5- H NMR (400 MHz, 00300) 5 ppm 8.14 HRMS(A) chloro—6-(2,2,2- (d, J=6.65 Hz, 1 H) 8.10 (d, J=1.96 Hz, 1 m/z trifluoroethoxy)pyridin H) 7.88 (d, J=2.35 Hz, 1 H) 7.57 (d, J=6.26 474.1523 y|)ethy|amino)pyrimidin Hz, 1 H)5.17 (d, J=6.65 Hz, 1 H)4.92 (q, (M+Hfi Isoprop | J=8.87 Hz, 1 H 4.80 - 4.84 m, 1H 2.04 Rt 2.18 methyloxazolidinone (br. s., 2 H) 1.55 (dd, J=15.85, 6.85 Hz, 6 (1:1 mixture of H) 0.79 (br.s., 6 H) diastereomers 502: (S)(2-(1-(5-ch|oro— (CD30D) 8.07 - 8.16 (m, 1 H) 7.89 (d, HRMS(A) 6-(2,2,2- J=1.96 Hz, 1 H) 7.32 (d, J=6.26 Hz, 1 H) m/z trifluoroethoxy)pyridin 5.08 (q, J=6.78 Hz, 1 H) 1.55 - 1.65 (m, 8 474.1534 y|)ethy|amino)pyrimidin H) 1.37 (d, J=11.35 Hz, 6 H) 1.20 (d, (M + H)+, 4,5,5- J=11.35 Hz, 3 H) Rt 2.16 tetramethyloxazolidin min 503: 3-(2-((S)(5-ch|oro— (CD30D) 8.47 (d, J=5.87 Hz, 1 H) 8.11 (d, HRMS(A) 6-(2,2,2- J=2.35 Hz, 3H) 7.99 (d, J=6.26 Hz, 1 H) m/z trifluoroethoxy)pyridin 7.88 (d, J=1.96 Hz, 3 H) 7.39 (d,J=6.26 Hz, 460.1375 y|)ethy|amino)pyrimidin 2 H) 7.32 (d, J=6.65 Hz, 2 H) 5.04 - 5.13 (M + H)+, y|)-4,4,5- (m, 1 H) 4.87 - 4.98 (m, 2 H) 4.45 (d, Rt 2.08, trimethyloxazolidinone J=6.65 Hz, 1 H) 4.35 (dd, J=13.69, 6.65 2.11 min (1:2 e of Hz, 2 H) 1.67(d, J=4.70 Hz, 9 H) 1.59 (d, reomers) J=7.04 Hz, 12 H) 1.39 (d, J=6.65 Hz, 3 H) 1.33 (t, J=6.06 Hz, 6 H) 0.99 - 1.27 (m, 9 504: (S)(2-(1-(5-ch|oro— (CD30D) 8.09 - 8.17 (m, 1 H) 7.88 (d, ) 6-(2,2,2- J=2.35 Hz, 1 H) 7.38 (d, J=6.26 Hz, 1 H) m/z trifluoroethoxy)pyridin 4.91 (q, J=8.61 Hz, 1 H) 4.06 - 4.16(m, 2 446.1219 y|)ethy|amino)pyrimidin H) 1.71 (m, 5 H) 1.58 (d, J=7.04 Hz, 3 H) (M + H)+, y|)-4,4-dimethyloxazolidin- 1.28 (br. s., 3 H) Rt 2.01 2-one min 505: (S)(2-(1-(2,5- (CD30D) 8.15 (d, J=3.13 Hz, 1 H) 6.92 - HRMS(A) difluoro—4- 7.08 (m, 2 H) 5.21 (q, J=6.78 Hz, 1 H) 4.44 m/z isopropylphenyl)ethylamin - 4.58 (m, 2 H) 4.10 - 4.22 (m, 1H) 3.96 (m, 381.1544 o)f|uoropyrimidin 1 H) 3.07 - 3.23 (m, 1 H) 1.48 (d, J=7.04 (M + H)+, y|)oxazolidinone Hz, 5 H) 1.21 (m, 6 H) Rt 2.26 506: (S)(2-(1-(4-bromo- (CD30D) 8.15 (d, J=3.52 Hz, 1 H) 7.39 (dd, HRMS(A) 2,5- J=9.00, 5.48 Hz, 1 H) 7.24 (dd, J=9.19, m/z difluoropheny|)ethy|amino) 6.46 Hz, 1 H) 5.19 (q, J=7.04 Hz,1 H) 4.44 417.018 f|uoropyrimidin - 4.58 (m, 2 H) 4.09 - 4.23 (m, 1 H) 3.94 (M + H)+, t y|)oxazolidinone (br. s., 1 H) 1.48 (d, J=7.04 Hz, 3 H) 2.07 min 507: (S)(2-(1-(3-(4- (CD30D) 8.09 (d, J=6.26 Hz, 1 H) 7.91 (d, HRMS(A) phenyl)—1,2,4- J=8.61 Hz, 2 H) 7.43 (d, J=8.61 Hz, 3 H) m/z oxadiazoI 5.35 (q, J=7.30 Hz, 1 H) 3.97 -4.09 (m, 2 87 y|)ethy|amino)pyrimidin H) 1.69 (d, J=7.43 Hz, 3 H) 1.62 (s, 3 H) (M + H)+, y|)-4,4-dimethyloxazolidin- 1.14 - 1.45 (m, 3 H) Rt 2.14 2-one min Example 508 N \ 0 HNAN/dNJJ\O A solution of 3-(2,6-dichloropyrimidinyl)-4,4-dimethy|oxazolidinone (70.0 mg, 0.267 mmol), (S)—(—)—1-phenylethanamine (0.034 mL, 0.267 mmol, 1.0 , and N-ethyl-N- isopropylpropanamine (0.070 mL, 0.401 mmol, 1.5 equiv) in DMSO (1.5 mL) was heated at 85 °C for 2-4 h. Purification by e phase HPLC provided the trifluoroacetate salt of (S)(6-chloro(1-phenylethylamino)pyrimidiny|)-4,4- dimethyloxazolidinone (20.0 mg, white solid) in 16% yield. 1H NMR (300 MHz, CDCI3) 8 7.36 (s, 1H), 7.33 — 7.31 (m, 4H),7.26 — 7.21 (m, 1H), 5.48 (br m, 1H), 4.02 — 3.94 (m, 2H), 1.65 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.26 (s, 3H); HRMS(A) m/z 347.1274 (M + H)+, Rt 2.32 min.
The compounds in Table 13 were prepared using methods similar to those described for the preparation of Example 508.
Table 13.
Table 14. al name, NMR chemical shifts and LCMS signal for each compound listed in Table 13.
Example: Name 1H NMR 400 MHz 5 . .m 509: (S)(6-chloro(1- ) 7.36 (s, 1H), 7.33 — 7.31 (m, HRMS(A) ethylamino)pyrimidi 4H),7.26 — 7.21 (m, 1H), 5.48 (br m, 1H), m/z nyl)—4,4- 4.02 — 3.94 (m, 2H), 1.65 (s, 3H), 1.55 (d, J 347.1274 dimethyloxazolidinone = 6.9 Hz, 3H), 1.26 (s, 3H) (M + H)? Rt 2.32 510: (S)(6-chloro(1- (CDCI3) 8.00 (d, J = 8.4 Hz, 2 H), 7.53 (s, HRMS(A) (3-(4-chlorophenyl)—1,2,4- 1H), 7.47 (d, J = 8.4 Hz, 2H), 5.44 — 5.29 m/z oxadiazol (br m, 1H), 4.09 — 4.02 (m, 2H), 1.78 (d, J 449.0905 yl)ethylamino)pyrimidin = 7.1 Hz, 3H), 1.72 (s, 3H), 1.40 (br s, 3H) (M + H)? yl)—4,4-dimethyloxazolidin- Rt 2.51 2-one min 511: (S)(6-chloro(1- (CDCI3) 8.00 (d, J = 8.7 Hz, 2H), 7.62 (s, HRMS(A) (3-(4-chlorophenyl)—1,2,4- 1H), 7.47 (d, J = 8.7 Hz, 2H), 5.32 (br m, m/z oxadiazol 1H), 4.49 — 4.43 (m, 2H), 4.17 — 4.14 (m, 421.0585 yl)ethylamino)pyrimidin 1H), 3.95 — 3.60 (br m, 1H), 1.77 (d, J = (M + H)? yl)oxazolidinone 7.1 Hz, 3H) Rt 2.32 512: (S)(6-chloro(1- (CDCI3) 7.76 (s, 1H), 7.60 (s, 1H), 7.50 (s, LCMS m/z (2-fluoro(1-methyl-1H- 1H), 7.34 — 7.28 (m, 1H), 7.20 (dd, J = 7.8, 417.2 pyrazol 1.6 Hz, 1H), 7.15 — 7.09 (m, 1H), 5.30 (br (M+H)+ yl)phenyl)ethylamino)pyri m, 1H), 4.49 — 4.42 (m, 2H), 4.28 — 4.23 midinyl)oxazolidin (m, 1H), 3.97 (s, 3H), 3.92 (br m, 1H), 1.56 one d, J = 6.7 Hz, 3H 513: (S)(2-(1-(3-(4- (CDCI3) 7.99 (d, J = 8.4 Hz, 2H), 7.45 (d, J HRMS(A) chlorophenyl)—1,2,4- = 8.4 Hz, 2H), 7.11 (s, 1H), 5.38 (br m, m/z oxadiazol 1H), 4.08 — 4.03 (m, 2H), 1.78 (d, J = 7.0 433.1201 yl)ethylamino)—6- Hz, 3H), 1.73 (s, 3H), 1.38 (br s, 3H) (M + H)? fluoropyrimidinyl)—4,4- Rt 2.42 dimeth loxazolidinone min Example 514: A solution of (S)(2-(1-(3-(4-ch|oropheny|)—1,2,4-oxadiazoIyl)ethylamino)—6- f|uoropyrimidiny|)-4,4-dimethy|oxazo|idinone (29.0 mg, 0.053 mmol) and 1 N aqueous hydrochloric acid (0.70 mL) in 1,4-dioxane (0.7 mL) was heated at 100 °C for 4 h. After cooling to room ature, the reaction mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over Na2804, filtered and concentrated. Purification by e phase HPLC provided the oroacetate salt of (S)(2-(1-(3-(4-ch|oropheny|)-1,2,4- oxadiazoIyl)ethylamino)—6-hydroxypyrimidiny|)-4,4-dimethyloxazolidinone (16 mg, white solid) in 55% yield. 1H NMR (400 MHz, CDCI3) 8 8.00 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 6.71 (br s, 1H), 5.33 (br m, 1H), 4.02 — 3.99 (m, 2H), 1.83 (d, J = 7.1 Hz, 3H), 1.68 (s, 3H), 1.31 (s, 3H); HRMS(A) m/z 431.1245 (M + H)+, Rt 1.80 min.
Example 515 Step 1 To round bottom flask containing ((S)—1-(2-f|uoro(1- methylcyclopropyl)phenyl)ethyl)—2-methylpropanesulfinamide (87 mg, 0.29 mmol) was added dioxane (2 mL). To this solution was added hydrochloric acid in dioxane (4.0M, 0.15 ml, 0.59 mmol) and the solution allowed to stir 10 min at room temperature.
Volatiles were d. EtZO (10 mL) was added and the reaction mixture sonnicated.
The volatiles were d again. EtZO (10 ml) was again added and the sion sonnicated. Solid material was ted and washed with EtZO to afford an HCI salt of (S)(2-fluoro(1-methylcyclopropyl)phenyl)ethanamine (42 mg, 0.18 mmol, 63 % yield) as a white solid. LCMS m/z 194.1 (M + H)+, Rt 0.60 min.
Step 2 To a microwave vial with stir bar was added (S)(2-chloropyrimidinyl)—4- isopropyloxazolidinone (30 mg, 0.12 mmol) and DMSO (1 mL). To this reaction mixture was added (S)(2-fluoro(1-methylcyclopropyl) phenyl)ethanamine (51 mg, 0.22 mmol) and DIEA (0.09 ml, 0.50 mmol). The vial was capped and the reaction mixture was heated in a preheated oil bath at 110 °C for 18 hr. Solution was purified by reverse phase HPLC. Product fractions combined, frozen and lyophilized to afford (S)- 3-(2-((S)—1-(2-f|uoro(1-methylcyclopropyl) phenyl) ethylamino) pyrimidinyl)—4- isopropyloxazolidinone (3.3 mg, 6.3 umol, 5 % yield) as a TFA salt. 1H NMR (400 MHz, CD30D) 8 0.58 (br. s., 3 H) 0.77 (td, J=5.23, 1.76 Hz, 5 H) 0.80 - 0.86 (m, 2 H) 1.38 (s, 3 H) 1.57 (d, J=6.94 Hz, 3 H) 4.34 - 4.41 (m, 2 H) 4.67 (br. s., 1 H) 5.33 (d, J=7.97 Hz, 1 H) 6.95 - 7.05 (m, 2 H) 7.22 (t, J=7.97 Hz, 1 H) 7.67 (d, J=6.85 Hz, 1 H) 8.14 (d, J=6.65 Hz, 1 H). LCMS m/z 399.4 (M + H)+, Rt 0.93 min. HRMS(A) m/z 399.2202 (M + H)+, Rt 2.23 min.
The compounds in Table 15 were prepared using methods similar to those described for the preparation of Examples 515.
Table 15.
WO 46136 WO 46136 Table 16. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 15.
Table 16.
Example: Name 1H NMR 400 MHz 8 ppm 516: (S)(2-((S)—1-(6- (DMSO) 0.46 (br. s., 3 H) 0.63 (br. s., 3 H) HRMS(A) tert-butylpyridinyl) 1.35 (s, 9 H) 1.50 (d, J=6.99 Hz, 3 H) 4.34 m/z mino)pyrimidinyl)— (d, J=7.92 Hz, 2 H) 4.59 (br. s., 1 H) 5.14 384.2410 4-isopropyloxazolidin (br. s., 1 H)7.32 (d, J=5.92 Hz, 1 H)7.70 (M+Hfi one (br. s., 1 H) 8.03 (br. s., 1 H) 8.24 (br. s., 2 Rt 1.34 H)8.59 (br. s., 1 H) 517: (S)(2-((S)—1-(6- (DMSO) 0.55 (br. s., 6 H) 1.25 - 1.38 (s, 9 HRMS(A) utylpyridin H) 1.47 (d, J=7.04 Hz, 3 H) 4.26 (br. s., 1 m/z yl)ethylamino) H) 4.45 - 4.59 (m, 2 H) 4.98 (br. s., 1 H) 402.2314 fluoropyrimidinyl)—4- 7.66 (br. s., 1 H)8.11 (br. s., 2 H)8.41 (br. (M+Hfi isopropyloxazolidinone s., 1 H)8.60 (br. s., 1 H) Rt 1.45 518: (S)isopropyl(2- HRMS(A) -(4-(1-methyl m/z cyclopropyl) 381.2295 phenyl)ethylamino)pyrimid (M+Hfi in | oxazolidinone Rt 2.10 519: (S)(2-((S)—1-(4- (DMSO) 0.49 (br. s., 3 H) 0.68 (br. s., 3 H) HRMS(A) (1 ,5-dimethyl-1 H-pyrazol- 1.48 (d, J=7.04 Hz, 8 H) 2.33 (s, 3 H) 3.76 m/z 4- (s, 3 H) 4.83 (br. s., 1 H) 4.75 - 4.82 (m, 1 421.2362 yl)pheny|)ethylamino)pyri H) 5.03 (br. s., 2 H) 7.30 - 7.37 (m, 4 H) (M+Hfi midinyl)—4- 7.50 (s, 1 H) 8.22 (br. s., 1 H) 8.36 (br. s., Rt 1.58 isoprop loxazolidinone 2012/055133 520: (2-((S)—1-(2- (DMSO) 0.40 (br. 3., 3 H) 0.57 (br. 3., 3 H) HRMS(A) fluoro (trif|uoromethy|) 1.40 (br. 3., 1 H) 1.47 (d, J=7.04 Hz, 3 H) m/z phenyl)ethylamino)pyrimid 4.24 - 4.37 (m, 2 H) 4.49 (br. 3., 1 H) 5.23 02 iny|) (br. 3., 1 H) 7.30 (d, J=5.82 Hz, 1 H) 7.48 - (M + H)+, i30propyloxazolidinone 7.59 (m, 2 H) 7.65 (d, J=10.56 Hz, 1 H) Rt 2.16 8.21 (d, J=18.58 Hz, 2 H) 521: (S)(2-((S)(4- (CD30D) 0.61 (br. 3., 3 H) 0.64 - 0.69 (m, 3 HRMS(A) cyclopropyI H) 0.77 (br. 3., 3 H) 0.96 - 1.04 (m, 2 H) m/z fluoropheny|)ethy|amino)p 1.57 (d, J=6.99 Hz, 3 H) 1.88 - 1.95 (m, 1 385.2042 yrimidiny|) H) 4.39 (d, J=5.97 Hz, 2 H) 4.69 (br. 3., 1 (M + H)+, i30propyloxazolidinone H) 5.33 (br. 3., 1 H) 6.82 (dd, J=12.08, Rt 2.06 1.71 Hz, 1 H) 6.88 (d, J=7.97 Hz, 1 H) 7.19 (t, J=8.31 Hz, 1 H) 7.70 (d, J=6.90 Hz, 1 H) 8.14 (d, J=7.04 Hz, 1 H) 522: (S)(2-((S)—1-(6- ) 0.65 - 0.83 (m, 6 H) 1.14 - 1.20 HRMS(A) cyclopropylpyridin (m, 2 H) 1.37 - 1.43 (m, 2 H) 1.64 (d, m/z y|)ethy|amino)pyrimidin J=7.09 Hz, 3 H) 2.26 - 2.37 (m, 1 H) 4.36 - 368.2097 y|)i30propy|oxazo|idin- 4.39 (m, 2 H) 4.68 (br. 3., 1 H) 5.25 (q, (M + H)+, 2-0ne J=6.75 Hz, 1 H) 7.57 (d, J=8.51 Hz, 1 H) Rt 1.12 7.63 (br. 3., 1 H) 8.18 (d, J=5.92 Hz, 1 H) 8.33 (d, J=7.24 Hz, 1 H) 8.57 (d, J=2.10 Hz, 1 H) 523: (S)i30propy|—3-(2- (CD30D) 0.59 - 0.84 (m, 6 H) 1.08 - 1.15 HRMS(A) ((S)(6-(1- (m, 2 H) 1.22 - 1.28 (m, 2 H) 1.56 (3, 3 H) m/z methylcyclopropy|)pyridin- 1.64 (d, J=7.09 Hz, 3 H) 4.35 - 4.39 (m, 2 382.2247 3-y|)ethy|amino)pyrimidin- H) 4.69 (br. 3., 1 H) 5.21 - 5.32 (m, 1 H) (M + H)+, 4-y|)oxazo|idinone 7.62 (br. 3., 1 H) 7.79 (d, J=8.46 Hz, 1 H) Rt 1.30 8.18 (d, J=6.11 Hz, 1 H) 8.33 (d, J=7.14 Hz, 1 H) 8.57 (d, J=2.20 Hz, 1 H) 524: (S)(2-((S)(4-(1- (CD30D) 0.60 (br. 3., 3 H) 0.78 (br. 3., 3 H) HRMS(A) ethoxycyclopropyl)—2- 0.92 - 0.98 (m, 2 H) 1.15 (t, J=7.07 Hz, 3 m/z fluoropheny|)ethy|amino)p H) 1.19 - 1.26 (m, 2 H) 1.59 (d, J=6.99 Hz, 429.2310 yrimidiny|) 3 H) 1.78 (br. 3., 1 H) 3.43 (q, J=7.09 Hz, 2 (M + H)+, i30propyloxazolidinone H) 4.40 (d, J=5.72 Hz, 2 H) 4.70 (d, J=3.91 Rt 2.08 Hz, 1 H) 5.38 (br. 3., 1 H) 7.06 (3, 1 H) 7.07 - 7.12 (m, 1 H) 7.31 (t, J=7.95 Hz, 1 H) 7.73 (d, J=7.04 Hz, 1 H) 8.15 (d, J=6.90 Hz, 1 H) 525: i30propy|—3-(2- (DMSO) 0.47 (br. 3., 3 H) 0.69 (br. 3., 3 H) HRMS(B) ((S)(4-(1-methy|—1H- 1.45 (d, J=6.99 Hz, 3 H) 1.81 (br. 3., 1 H) m/z pyrazoI 3.84 (3, 3 H) 4.33 (d, 5 Hz, 2 H) 407.2179 y|)pheny|)ethylamino)pyri 4.62 (br. 3., 1 H) 4.99 (br. 3., 1 H) 7.24 - (M + H)+, midiny|)oxazo|idin 7.33 (m, 3 H) 7.46 (d, J=8.27 Hz, 2 H) 7.79 Rt one (d, J=0.73 Hz, 1 H) 8.06 (3, 1 H) 8.18 (br. 2.44min 3., 1 H) 526: (S)(2-((S)—1-(2- (CD30D) 0.59 (br. 3., 3 H) 0.78 (br. 3., 3 H) HRMS(A) fluoro 1.23 (dd, J=6.90, 1.03 Hz, 6 H) 1.58 (d, m/z i30prop Iphen | eth lamin J=6.99 Hz, 3 H 2.91 dt, J=13.78, 6.93 Hz, 387.2207 o)pyrimidinyl)—4- 1 H) 4.39 (d, J=5.97 Hz, 2 H) 4.69 (br. 3., 1 isopropyloxazolidinone H) 5.35 (br. 3., 1 H) 6.97 - 7.06 (m, 2 H) 7.20 - 7.28 (m, 1 H) 7.73 (d, J=6.99 Hz, 1 H) 8.15 (d, J=6.90 Hz, 1 H) 527: 1-(3-fluoro((S)—1- (CD30D) 0.61 (br. 3., 3 H) 0.75 (br. 3., 3 H) HRMS(A) (4-((S)i30propy|—2- 1.40 - 1.50 (m, 2 H) 1.57 (d, J=6.94 Hz, 3 m/z oxooxazolidin H) 1.71 - 1.79 (m, 2 H) 4.37 (d, J=6.50 Hz, 410.1999 y|)pyrimidinylamino) 2 H) 4.66 (br. 3., 1 H) 5.34 (d, J=6.55 Hz, 1 (M + H)+, ethyl)pheny|)cyclopropane H) 7.07 - 7.18 (m, 2 H) 7.36 (t, J=8.19 Hz, Rt 1.82 carbonitrile 1 H) 7.64 (d, J=6.65 Hz, 1 H) 8.15 (d, J=6.60 Hz, 1 H) 528: (S)(2-((S)—1-(2- ) 0.58 (br. 3., 3 H) 0.78 (br. 3., 3 H) HRMS(A) fluoro—4-(1-methyI-1H- 1.62 (d, J=7.04 Hz, 3 H) 1.82 (br. 3., 1 H) m/z pyrazoI 3.92 (3, 3 H) 4.40 (d, J=6.26 Hz, 2 H) 4.70 425.2112 y|)phenyl)ethylamino)pyri (br. 3., 1 H) 5.39 (br. 3., 1 H) 7.29 - 7.39 (M + H)+, 4-y|) (m, 3 H) 7.78 (d, J=7.04 Hz, 1 H) 7.82 (3, 1 Rt 1.64 isopropyloxazolidinone H) 7.99 (3, 1 H) 8.16 (d, J=7.04 Hz, 1 H) 529: (S)(2-((S)—1-(2- (CD30D) 0.59 (br. 3., 3 H) 0.79 (br. 3., 3 H) HRMS(A) fluoro—4-(1H-pyrazoI 1.63 (d, J=6.94 Hz, 3 H) 1.84 (br. 3., 1 H) m/z y|)phenyl)ethylamino)pyri 4.40 (d, J=6.26 Hz, 2 H) 4.71 (br. 3., 1 H) 411.1949 midiny|) 5.40 (br. 3., 1 H) 7.29 - 7.36 (m, 1 H) 7.37 - (M + H)+, isopropyloxazolidinone 7.43 (m, 2 H) 7.78 (d, J=7.09 Hz, 1 H) 7.99 Rt 1.52 (3,2 H) 8.17 (dd, J=6.36, 1.86 Hz, 1 H) 530: 2-chloro-N- (DMSO) 0.55 (br. 3., 3 H) 0.78 (br. 3., 3 H) HRMS(A) cyclopentyI((S)(4- 1.42 (d, J=7.09 Hz, 3 H) 1.50 (d, J=4.65 m/z ((S)i30propy|—2- Hz, 4 H) 1.64 (br. 3., 2 H) 1.83 (d, J=6.46 472.2117 oxooxazolidin Hz, 3 H) 4.14 (dd, J=12.72, 6.60 Hz, 1 H) (M + H)+, y|)pyrimidin 4.34 (br. 3., 2 H) 4.64 (br. 3., 1 H) 5.03 (br. Rt 1.82 y|amino)ethy|)benzamide 3., 1 H) 7.25 (d, J=5.77 Hz, 1 H) 7.31 (3, 2 H) 7.42 (3, 1 H) 8.19 (br. 3., 1 H) 8.27 (br. 3., 1 H) 531: 2-chloro—N- (DMSO) 0.55 (br. 3., 3 H) 0.78 (br. 3., 4 H) HRMS(A) exyI((S)(4- 1.18 - 1.34 (m, 4 H) 1.42 (d, J=7.04 Hz, 3 m/z ((S)i30propy|—2- H) 1.56 (d, J=12.08 Hz, 1 H) 1.69 (d, 486.2275 oxooxazolidin J=12.86 Hz, 3 H) 1.81 (br. 3., 3 H) 4.34 (br. (M + H)+, imidin 3., 2 H) 4.63 (br. 3., 1 H) 5.03 (br. 3., 1 H) Rt 1.94 y|amino)ethy|)benzamide 7.26 (d, J=5.82 Hz, 1 H) 7.31 (3, 2 H) 7.43 (3, 1 H) 8.03 (br. 3., 1 H) 8.18 (br. 3., 2 H) 532: 2-chloro—N-((1r,4S)— (DMSO) 0.54 (br. 3., 3 H) 0.77 (br. 3., 3 H) HRMS(A) 4-hydroxycyclohexyl)—4- 1.18 - 1.30 (m, 5 H) 1.36 (3, 1 H) 1.42 (d, m/z ((S)(4-((S)i30propy|— J=7.04 Hz, 3 H) 1.81 (d, J=9.19 Hz, 5 H) 502.2226 xazolidin 3.36 (br. 3., 1 H) 4.33 (br. 3., 2 H) 4.63 (br. (M + H)+, y|)pyrimidin 3., 1 H) 5.02 (br. 3., 1 H) 7.25 (d, J=5.77 Rt 1.40 y|amino)ethy|)benzamide Hz, 1 H) 7.30 (3, 2 H) 7.42 (3, 1 H) 8.17 (br. 3., 2 H) 533: (S)(2-((S)—1-(3- (DMSO) 0.40 - 0.73 (m, 6 H) 1.40 (d, HRMS(A) pentyloxy)pheny|)et J=6.99 Hz, 3 H) 1.47 - 1.70 (m, 6 H) 1.83 m/z h lamino p rimidin |- dd, J=16.80, 6.72 Hz, 3 H 4.31 d,J=8.75 411.2402 4-isopropyloxazolidin Hz, 2 H)4.58 (br. s., 1 H)4.71 (br. s., 1 H) one 4.94 (br. s., 1 H) 6.69 (dd, J=7.95, 2.03 Hz, 1 H) 6.81 (d, J=8.31 Hz, 2 H) 7.09 - 7.19 (m, 1 H)7.27 (d, J=6.06 Hz, 1 H)8.16 (br. 534: (S)(2-((S)—1-(3- (DMSO) 0.47 (br. s., 3 H) 0.65 (br. s., 3 H) HRMS(A) (cyclohexyloxy)phenyl)eth 1.14 - 1.36 (m, 5 H) 1.40 (d, J=7.04 Hz, 3 m/z ylamino)pyrimidiny|) H) 1.44 - 1.54 (m, 1 H) 1.65 (d, J=9.34 Hz, 425.2565 isopropyloxazolidinone 2 H) 1.72 - 1.91 (m, 3 H) 4.11 -4.39 (m, 3 (M+Hfi H) 4.57 (br. s., 1 H) 4.94 (br. s., 1 H) 6.71 Rt 2.26 (dd, J=7.85, 1.88 Hz, 1 H) 6.80 (br. s., 2 H) min 7.14 (t, J=8.07 Hz, 1 H) 7.26 (d, J=6.02 Hz, 1H 8.16 br. s., 2 H 535: (S)(2-((S)—1-(3- (DMSO) 0.50 (br. s., 3 H) 0.68 (br. s., 3 H) HRMS(A) (cycloheptyloxy)pheny|)et 1.43 (d, J=7.04 Hz, 5 H) 1.53 (d, J=2.98 m/z hylamino)pyrimidinyl)— Hz, 4 H) 1.58 - 1.71 (m, 4 H) 1.73 - 1.97 439.2712 4-isopropyloxazolidin (m, 3 H) 4.34 (d, J=8.46 Hz, 2 H) 4.38 - (M+Hfi one 4.46 (m, 1 H) 4.60 (br. s., 1 H) 4.98 (br. s., Rt 2.41 1 H) 6.70 (dd, J=8.14, 2.03 Hz, 1 H) 6.76 - min 6.89 (m, 2 H) 7.18 (t, J=7.87 Hz, 1 H) 7.30 d, J=6.02 Hz, 1 H 8.20 br. s., 2 H 536: (S)(2-((S)—1-(3- (DMSO) 0.49 (br. s., 3 H) 0.67 (br. s., 3 H) HRMS(A) isopropoxyphenyl)ethylam 1.09 - 1.28 (m, 7 H) 1.32 - 1.50 (m, 3 H) m/z ino)pyrimidinyl)—4- 4.23 - 4.39 (m, 2 H) 4.52 (dt, J=12.04, 6.08 385.2248 isopropyloxazolidinone Hz, 1 H)4.60 (br. s., 1 H)4.96 (br. s., 1 H) (M+Hfi 6.71 (dd, J=8.00, 1.98 Hz, 1 H) 6.82 (br. s., Rt 1.92 2H) 7.15 (t, J=8.09 Hz, 1 H) 7.30 (d, min J=6.02 Hz, 1 H)8.18 (br. s., 1 H)8.28 (br. 537: (S)(5-f|uoro((S)— (DMSO) 0.49 (br. s., 6 H) 0.92 (d, J=6.7 HRMS(A) 1-(3- Hz, 6 H) 1.37 (d, J=7.04 Hz, 3 H) 1.93 m/z isobutoxyphenyl)ethylami (dquin, J=13.25, 6.60, 6.60, 6.60, 6.60 Hz, 417.231 no)pyrimidinyl)—4- 1 H) 3.59 - 3.70 (m, 2 H) 3.94 - 4.31 (m, 3 (M+Hfi isopropyloxazolidinone H) 4.45 (br. s., 1 H) 6.69 (dd, J=8.17, 1.76 Rt 2.53 Hz, 1 H) 6.80 - 6.89 (m, 2 H) 7.13 (t, min J=7.83 Hz, 1H) 7.92 (br. s., 1 H) 8.34 (br. 538: (S)(5-f|uoro((S)— (DMSO) 1.41 (d, J=7.04 Hz, 6 H) 1.83 - HRMS(A) 1-(3-((S)—tetrahydrofuran- 1.93 (m, 1 H)2.11 -2.23 (m, 1 H) 3.68 - m/z 3- 4.04 (m, 8 H) 4.25 (br. s., 1 H) 4.49 (br. s., 98 y|oxy)pheny|)ethy|amino)p 2 H) 4.80 (br. s., 1 H) 4.95 (dd, J=6.06, (M+Hfi yrimidinyl)—4- 4.65 Hz, 1 H) 6.72 (dd, J=8.02, 2.10 Hz, 1 Rt 2.01 pyloxazolidinone H) 6.83 - 6.94 (m, 2 H) 7.19 (t, J=7.87 Hz, min 1 H 7.96 br. s., 1 H 8.38 br. s., 1 H 539: (4S)—4-isopropy|—3-(2- (DMSO) 0.47 (br. s., 3 H) 0.66 (br. s., 3 H) HRMS(A) ((1S)—1-(3-(tetrahydro—2H- 1.39 (d, J=6.99 Hz, 3 H) 1.44 - 2.00 (m, 5 m/z pyran H) 3.32 - 3.50 (m, 2 H) 3.54 - 3.88 (m, 3 H) 53 y|oxy)pheny|)ethy|amino)p 4.23 - 4.37 (m, 2 H) 4.61 (br. s., 1H) 4.90 (M+Hfi yrimidinyl)oxazolidin (br. s., 1H) 6.74 (d, J=8.36 Hz, 1 H) 6.85 Rt 1.75 one (d, J=13.55 Hz, 2 H) 7.15 (t, J=7.87 Hz, 1 min H) 7.25 (d, J=5.97 Hz, 1 H) 8.06 (br. s.,1 H 8.16 br. s., 1 H 540: (S)isopropy|—3-(2- (DMSO) 0.50 (br. s., 3 H) 0.66 (br. s., 3 H) ) «$443 1.42 (d, J=7.04 Hz, 3 H) 1.75 (br. s., 1 H) m/z phenox phen Ieth lamin 4.27 - 4.37 m, 2 H 4.55 - 4.62 m, 1 H 419.2092 o)pyrimidin 4.97 -5.07 (m, 1 H) 6.78 (dd, J=8.02, 1.81 zo|idinone Hz, 1 H) 6.87 (d, J=7.53 Hz, 2 H) 6.96 (br. s., 1 H) 7.04 - 7.14 (m, 2 H) 7.25 - 7.37 (m, 4 H) 8.17 (d, J=4.99 Hz, 1 H) 8.36 (br. s., 1 541: (S)(5-f|uoro—2-((S)— (DMSO) 0.44 - 0.65 (m, 6 H) 1.37 (d, HRMS(A) 1-(3- J=6.99 Hz, 3 H) 4.08 - 4.40 (m, 2 H) 4.45 m/z phenoxyphenyl)ethy|amin (br. s., 1 H) 4.82 (br. s., 1 H) 8.75 (dd, 437.1992 o)pyrimidinyl)—4- J=8.07, 1.37 Hz, 1 H) 6.86 (d, J=7.48 Hz, 2 (M+Hfi pyloxazolidinone H)6.95 (br. s., 1 H)7.03-7.11 (m, 2 H) Rt 2.45 7.28 (dt, J=19.78, 7.86 Hz, 3 H) 7.94 (br. min s., 1 H 8.33 br. s.,1 H 542: (S)(5-f|uoro—2-((S)— (DMSO) 0.56 (br. s., 6 H) 1.18 (d, J=2.35 HRMS(A) 1-(4- Hz, 3 H) 1.20 (d, J=2.30 Hz, 3 H) 1.36 (d, m/z isopropoxyphenyl)ethylam J=7.04 Hz, 3 H) 4.21 (br. s., 1H) 4.38 - 403.2156 ino)pyrimidinyl)—4- 4.58 (m, 3 H) 4.75 (br. s., 1H) 8.77 (d, (M+Hfi isopropyloxazolidinone J=8.71 Hz, 2 H) 7.18 (d, J=8.56 Hz, 2 H) Rt 2.30 7.87 br. s., 1 H 8.33 d, J=2.74 Hz, 1 H min 543: (4S)—4-isopropy|—3-(2- (CD30D) 8.00 - 8.17 (m, 1H), 7.71 (d, J = HRMS(A) ((1-(tetrahyd rofu ran 7.04 Hz, 1H), 4.78 - 4.85 (m, 1H), 4.41 - m/z y|)ethy|)amino)pyrimidin 4.55 (m, 2H), 3.98 - 4.14 (m, 1H), 3.84 - 321.1935 y|)oxazo|idinone 3.97 (m, 1H), 3.67 - 3.82 (m, 1H), 2.55 - W+Hfi 2.70 (m, 1H), 1.86 - 2.13 (m, 3H), 1.56 - Rt 1.32 1.82 (m, 1H), 1.24 - 1.34 (m, 3H), 1.00 - min 1.06 m, 3H ,0.91 t, J: 6.06 Hz, 3H 544: (S)(2-((S)—1-(4- (400 MHz, DMSO) 8 ppm 0.54 (br. s., 3 H) HRMS(A) isobutoxy 0.72 (br. s., 3 H) 0.96 (d, J=6.70 Hz, 6 H) m/z methylphenyl)ethylamino) 1.41 (d, J=6.99 Hz, 3 H) 1.89 (br. s., 1 H) 413.2561 pyrimidinyl)—4- 1.99 (dt, J=13.24, 6.61 Hz, 1 H) 2.11 (s, 3 W+Hfi isopropyloxazolidinone H) 3.68 (d, J=6.41 Hz, 2 H) 4.31 - 4.41 (m, Rt 2.34 2 H) 4.62 (dd, , 3.72 Hz, 1 H) 4.94 min (quin, J=6.94 Hz, 1 H)6.80 (d, J=8.31 Hz, 1 H) 7.00 - 7.13 (m, 2 H) 7.34 (d, J=6.06 Hz, 1 H)8.19 (d, J=4.94 Hz, 1 H)8.42 (br. 545: (2-((S)—1-(6-(1- H NMR (400 MHz, 00300) d 0.65 (br. s., HRMS(A) ethoxycyclopropyl)pyridin- 3 H) 0.75 (br. s., 3 H) 1.23 (t, J=7.04 Hz, 3 m/z 3-y|)ethy|amino)pyrimidin- H) 1.28 - 1.45 (m, 4 H) 1.64 (d, J=7.09 Hz, 412.2349 4-y|) 3 H) 3.55 (q, J=7.04 Hz, 2 H) 4.36 - 4.43 W+Hfi isopropyloxazolidinone (m, 2 H) 4.70 (br. s., 1 H) 5.20 - 5.28 (m, 1 Rt 1.55 H) 7.66 (d, J=8.41 Hz, 2 H) 8.04 (br. s., 1 min H 8.16 d, J=6.41 Hz, 1 H 546: (2-((S)—1-(4- H NMR (400 MHz, DMSO) d ppm 0.54 HRMS isobutoxy (br. s., 3 H) 0.72 (br. s., 3 H) 0.96 (d, m/z methylphenyl)ethylamino) J=6.70 Hz, 6 H) 1.41 (d, J=6.99 Hz, 3 H) 413.2561 pyrimidinyl)—4- 1.89 (br. s., 1 H) 1.99 (dt, J=13.24, 6.61 W+HW isopropyloxazolidinone Hz, 1 H)2.11 (s, 3 H)3.68 (d, J=6.41 Hz, 2 Rt-2.34 H) 4.31 - 4.41 (m, 2 H) 4.62 (dd, J=6.99, min. 3.72 Hz, 1 H) 4.94 (quin, J=6.94 Hz, 1 H) 6.80 (d, J=8.31 Hz, 1 H) 7.00 - 7.13 (m, 2 H) 7.34 (d, J=6.06 Hz, 1 H) 8.19 (d, J=4.94 Hz, 1 H 8.42 br.s., 1 H Example 547 [00*W A solution of (S)(2-((S)—1-(4-(ch|oromethy|)phenyl)ethylamino)pyrimidiny|)—4- isopropyloxazolidinone (75 mg, 0.2 mmol) and 5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine (25 mg, 0.2 mmol) in DMSO (2 mL) was heated at 80 °C for 16 h. The reaction e was diluted with EtOAc (20 mL) and washed with water (20 mL). After separation, the s phase was washed with EtOAc (2 x 15 mL). ed organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH in CH2C|2 0 to 10%) provided (S)(2-((S)(4-((5,6-dihydroimidazo[1,2- a]pyrazin-7(8H)-y|)methy|)pheny|)ethy|amino)pyrimidinyl)isopropy|oxazo|idinone (58 mg, white solid) in 62.8% yield. 1H NMR (400 MHz, MeOD) 6 8.12 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 5.9 Hz, 1H), 7.33 (s, 4H), 6.99 (d, J = 1.3 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 5.07 (q, J = 7.0 Hz, 1H), 4.68 (br s, 1H), 4.37 — 4.25 (m, 2H), 4.02 (t, J = 5.5 Hz, 2H), 3.72 (s, 2H), 3.63 (s, 2H), 2.90 (td, J = 5.4, 2.6 Hz, 2H), 1.84 (br s, 1H), 1.51 (d, J = 7.0 Hz, 3H), 0.72 (br s, 3H), 0.57 (br s, 3H); HRMS m/z 462.2606 (M + H)+.
The following compounds were prepared using methods similar to those described for the preparation of Example 205.
Example 548 WIT/UL 00*W (4S)—3-(2-((1S)—1-(4-(3,8-diazabicyclo[4.2.0]octan ylmethyl)phenyl)ethylamino)pyrimidinyl)isopropy|oxazo|idinone. 1H NMR (400 MHz, MeOD) 6 8.12 — 8.08 (m, 1H), 7.37 — 7.22 (m, 5H), 5.10 — 5.01 (m, 1H), 4.66 (br s, 1H), 4.37 — 4.23 (m, 2H), 3.92 — 3.89 (m, 1H), 3.63 — 3.54 (m, 1H), 3.54 — 3.47 (m, 1H), 3.24 — 3.20 (m, 1H), 3.11 — 2.95 (m, 1H), 2.95 — 2.73 (m, 1H), .2.67 — 2.59 (m, 2H), 2.49 (ddd, J = 16.2, 12.8, 5.3 Hz, 1H), 2.20 — 2.08 (m, 1H), 1.99 — 1.68 (m, 3H), 1.50 (d, J = 7.0 Hz, 3H), 0.72 (br S, 1H), 0.56 (br S, 1H) ; HRMS m/z 451.2810 (M + H)+.
Example 549 milkN/ 0 “042* 1““ (S)—3-(2-((S)—1-(4-((4-aminopiperidiny|)methyl)phenyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone. 1H NMR (400 MHz, MeOD) d 8.12 (d, J = 5.8 Hz, 1H), 7.34 (d, J = 5.8 Hz, 1H), 7.27 (q, J = 8.2 Hz, 4H), 5.05 (q, J = 7.0 Hz, 1H), 4.67 (s, 1H), 4.38 - 4.25 (m, 2H), 3.48 (s, 2H), 2.86 (br d, J = 11.8 Hz, 2H), 2.71 (tt, J = 10.9, 4.2 Hz, 1H), 2.05 (tt, J = 12.0, 2.5 Hz, 2H), 1.90 - 1.75 (m, 3H), 1.54 - 1.37 (m, 5H), 0.72 (br s, 4H), 0.55 (br s, 3H); HRMS m/z 439.2805 (M + H)+.
The ing compounds were prepared using methods similar to those described for the preparation of Example 210.
Example550 “1 ° HNJ\\N NA “Owfi W” (S)(2-((S)—1-(4-((4-hydroxymethylpiperidiny|)methyl)phenyl)ethylamino)pyrimidin- 4-yl)isopropyloxazolidinone. 1H NMR (400 MHz, MeOD) 6 8.12 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 5.9 Hz, 1H), 7.27 (t, J = 6.6 Hz, 4H), 5.06 (q, J = 6.8 Hz, 1H), 4.67 (br s, 1H), 4.37 — 4.25 (m, 2H), 3.51 (d, J = 3.2 Hz, 2H), 2.52 (br s, 2H), 2.44 (br s, 2H), 1.81 (br s, 1H), 1.59 (br s, 4H), 1.50 (d, J = 7.0 Hz, 3H), 1.19 (s, 3H), 0.72 (br s, 3H), 0.56 (br s, 3H); HRMS m/z 454.2816 (M + H)+.
Example 552 NNiT/ILNJL 60*W (S)(2-((S)—1-(4-((3,3-difluoropiperidiny|)methyl)phenyl)ethylamino)pyrimidiny|) isopropyloxazolidinone. 1H NMR (400 MHz, MeOD) 6 8.12 (d, J = 5.8 Hz, 1H), 7.35 (d, J = 5.8 Hz, 1H), 7.28 (q, J = 8.2 Hz, 4H), 5.06 (q, J = 7.0 Hz, 1H), 4.67 (br s, 1H), 4.39 — 4.25 (m, 2H), 3.55 (d, J = 2.2 Hz, 2H), 2.56 (t, J = 11.5 Hz, 2H), 2.51 — 2.40 (m, 2H), 1.91 — 1.81 (m, 3H), 1.78 — 1.70 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H), 0.71 (br s, 3H), 0.56 (br s, 3H) ; HRMS m/z 460.2537 (M + H)+.
Example 553 NNiC'LNJZ ““5N0*W (S)(2-((S)—1-(4-(4,7-diazaspiro[2.5]octany|methyl)phenyl)ethylamino)pyrimidiny|)- ropyloxazolidinone 1H NMR (400 MHz, MeOD) 6 8.12 (d, J = 5.8 Hz, 1H), 7.34 (d, J = 5.8 Hz, 1H), 7.32 — 7.24 (m, 4H), 5.06 (q, J = 7.0 Hz, 1H), 4.68 (br s, 1H), 4.37 — 4.26 (m, 2H), 3.49 (s, 2H), 2.89 (t, J = 5.0 Hz, 2H), 2.47 (br s, 2H), 2.28 (br s, 2H), 1.86 (br s, 1H), 1.49 (d, J = 7.0 Hz, 3H), 0.72 (br s, 3H), 0.64 — 0.49 (m, 5H), 0.45 (t, J = 3.2 Hz, 2H) ; HRMS m/z 451.2809 (M + H)+.
Example 554 (S)(2-((S)—1-(4-(4,7-diazaspiro[2.5]octanylmethyl)phenyl)ethylamino)pyrimidinyl)— 4-isopropyloxazolidinone. 1H NMR (400 MHz, MeOD) 6 8.11 (d, J = 5.8 Hz, 1H), 7.33 (d, J = 5.8 Hz, 1H), 7.24 (q, J = 8.3 Hz, 4H), 5.03 (q, J = 7.0 Hz, 1H), 4.67 (br s, 1H), 4.37 — 4.25 (m, 2H), 3.85 (s, 2H), 2.85 — 2.65 (m, 6H), 1.87 (br s, 1H), 1.48 (d, J = 7.0 Hz, 3H), 0.85 — 0.63 (m, 5H), 0.63 — 0.46 (m, 5H); HRMS m/z 451.2810 (M + H)+.
Example 555 NNifiNi (S)isopropyl(2-((S)—1-(4-((3,3,4,4-tetrafluoropyrrolidinyl)methyl)phenyl) ethylamino)pyrimidinyl)oxazolidinone.
HRMS m/z 482.2161 (M + H)+; RT=2.78 min.
Example 556 NNDLNJE *00*WL (S)(2-((S)—1-(4-((4-acetylpiperaziny|)methyl)phenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone.
HRMS m/z 467.2752 (M + H)+; RT=1.92 min.
Example 557 NNJNLN: \‘N‘ (S)—4,6-difluoro-N-(1-phenylethy|)pyrimidinamine (48.8 mg, 0.21 mmol) was added to NaH (95 %, 6.1 mg, 0.25 mmol, 1.2 equiv) in DMF (2 mL) at 0 °C. After 5 min, (S) isopropyloxazolidinone (27.9 mg, 0.22 mmol, 1.0 equiv) was added. The on was stirred for 10 min at 0 °C and then warmed to room temperature. After 4h, the reaction mixture was quenched with water and poured into dilute brine (1:1 sat. brine:water) and EtOAc. The s phase was ted with EtOAc and the combined organic layers were washed with diluted brine. The organic layer was dried over , filtered and concentrated to a pink oil. Purification by reverse phase HPLC followed by lyopholization of the fractions containing product provided (S)(6-fluoro(((S)—1- phenylethyl)amino)pyrimidinyl)isopropyloxazolidinone as a white solid (22.5 mg TFA salt) in 31% yield. 1H NMR (400 MHz, CD30D) 8 7.27 - 7.39 (m, 4H), 7.17 - 7.26 (m, 1H), 6.92 (s, 1H), 5.05 (q, J = 7.04 Hz, 1H), 4.63 (br. s., 1H), 4.19 - 4.41 (m, 2H), 1.77 (br. s., 1H), 1.51 (d, J = 7.04 Hz, 3H), 0.44 - 0.78 (m, 6H); LCMS m/z 345.1 (M + H)+., R 1.00 min; UPLC Rt 5.038 min.
The compounds in Table 17 were prepared using methods similar to those described for the preparation of Example 557.
Table 17.
Table 18: Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 17.
Example: Name 1H NMR 400 MHz 8 ppm _ 558: (S)—5,5-dimethyl (CD30D) 8.06 (d, J = 5.8 Hz, 1 H), 7.43 (d, HRMS(A) phenyl(2-((S)—1- J = 5.8 Hz, 1 H), 7.31 — 7.24 (m, 3 H), 7.19 m/z phenylethylamino)pyrimidi — 7.11 (m, 5 H), 7.01 (br s 2 H), 5.48 (s, 1 389.1987 nyl)oxazolidinone H), 4.86 — 4.80 (m, 1 H), 1.65 (s, 3 H), 1.43 (M + H)+ d,J=7.0Hz,3H,0.98 s,3H Example 559 N HfiN / \Ir ; \ N - N .@ 07g) A mixture of (R)—3-(2-chloropyrimidinyl)pheny|oxazolidinone (55.3 mg, 0.20 mmol), (S)—1-cyclopropylethylamine (40 uL, 0.26 mmol, 1.3 equiv) and iPr2Net (0.20 mL, 1.15 mmol, 5.7 equiv) in NMP (1 mL) was heated in the microwave at 180 °C for 20min.
The reaction mixture was filtered and ed by reverse phase HPLC to give (2- (((S)cyclopropylethyl)amino)pyrimidinyl)—4-phenyloxazolidinone as a white solid (8.8 mg) in 10 % yield. 1H NMR (400 MHz, CD30D) 8 7.72 (d, J = 6.26 Hz, 1H), 7.29 - 7.43 (m, 6H), 5.76 (dd, J = 4.11, 8.80 Hz, 1H), 4.28 (dd, J = 4.30, 8.61 Hz, 1H), 3.06 - 3.19 (m, 1H), 1.39 (dd, J = 3.52, 6.65 Hz, 1H), 0.88 - 0.97 (m, 1H), 0.83 (br. s., 3H), 0.53 - 0.62 (m, 1H), 0.50 (dt, J = 4.11, 8.51 Hz, 1H), 0.33 (qd, J = 4.78, 9.54 Hz, 1H), 0.26 (td, J = 4.60, 9.59 Hz, 1H); HRMS(A) m/z 325.1667 (M + H)+, Rt 1.54 min; UPLC 2.807 min.
The compounds in Table 19 were prepared using methods similar to those described for the preparation of Example 559.
Table 19.
Table 20. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 19.
WO 46136 —_-__ 560: (S)benzyl(2- (CD30D) 8.13 (d, J = 7.04 Hz, 1H), 7.71 (d, HRMS(A) (((S) J = 7.04 Hz, 1H), 7.22 - 7.38 (m, 5H), 5.11 m/z cyclopropylethyl)amino)py (tt, J = 3.03, 8.12 Hz, 1H), 4.23 -4.53 (m, 22 rimidinyl)oxazolidin 2H), 3.08 (dd, J = 8.41, 13.50 Hz, 1H), (M + H)+, one 1.42 (d, J = 6.65 Hz, 3H), 1.04 - 1.23 (m, Rt 1.64 1H), 0.47 - 0.73 (m, 2H), 0.17 - 0.47 (m, min 561: (S)(5-fluoro ) (((S)'1 '(3' m/z isopropylphenyl)ethyl)ami 387.2203 no)pyrimidinyl)—4- (M + H)+, isopropyloxazolidinone Rt 2.52 562: (S)(2-(((S)—1-(4- HRMS(A) chlorophenyl)ethyl)amino) m/z f|uoropyrimidinyl)—4- 379.1341 isopropyloxazolidinone (M + H)+, Rt 2.30 Example 563 N 5 o7%17* A mixture of (S)(2-chloropyrimidinyl)isopropy|oxazolidinone (43.2 mg, 0.18 mmol), (1S)—1-[4-(2-Methy|propoxy)phenyl]ethanamine (84.0 mg, 0.37 mmol, 2.0 equiv) and iPr2Net (0.30 mL, 1.72 mmol, 4.7 equiv) in NMP (1 mL) was heated at 105 °C for 24 h. The reaction mixture was filtered and purified by reverse phase HPLC to give (S)—3-(2-(((S)—1-(4-isobutoxyphenyl)ethyl)amino)pyrimidinyl)isopropyloxazolidin one as a white solid (5.3 mg, TFA salt) in 4 % yield. 1H NMR (400 MHz, CD30D) 8 7.68 (d, J = 6.65 Hz, 1H), 7.25 (d, J = 8.61 Hz, 2H), 6.90 (d, J = 8.61 Hz, 2H), 4.41 (d, J = .87 Hz, 2H), 3.74 (d, J = 6.26 Hz, 2H), 1.96 - 2.15 (m, 1H), 1.58 (d, J = 7.04 Hz, 3H), 1.03 (d, J = 6.65 Hz, 6H); HRMS(A) m/z 399.2399 (M + H)+, Rt 2.60 min; UPLC 4.223 min.
The compounds in Table 21 were prepared using methods r to those described for the preparation of Example 563. 2012/055133 Table 21.
Table 22. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 21.
Example: Name 1H NMR 400 MHz 8 ppm 564: (S)(5-fluoro ) (((S)(4- m/z isobutoxyphenyl)ethyl)ami 417.2314 no)pyrimidinyl)—4- (M + H)+, isopropyloxazolidinone Rt 2.53 565: (S)(5-fluoro HRMS(A) (((S)(2-fluoro(1- m/z methyl-1H-pyrazol 12 yl)phenyl)ethyl)amino)pyri (M + H)+, 4-yl) Rt 1.92 isoprop loxazolidinone min Example 566 N NHQ o .
/ N F To a microwave vial with stir bar was added (S)—3-(2-chloropyrimidinyl)—4- isopropyloxazolidinone (24.96 mg, 0.103 mmol) in DMSO (1653 uL). To this reaction mixture was added (S)—1-(2,3-difluorophenyl)ethanamine (40 mg, 0.207 mmol) and DIEA (144 uL, 0.826 mmol). The vial capped and heated at 110 °C over the weekend. The solution was filtered, then purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford ((S)(2-((S)—1-(2,3-difluorophenyl)ethylamino) pyrimidinyl)isopropyloxazolidinone (10.2 mg, 0.021 mmol, 10.26 % yield) as a TFA salt. 1H NMR (400 MHz, CD30D) 5 ppm 0.59 (br. s., 3 H) 0.75 (br. s., 3 H) 1.59 (d, J=6.99 Hz, 3 H) 1.59 (br. s., 1 H) 4.37 (d, J=5.67 Hz, 2 H) 4.66 (br. s., 1 H) 5.40 (d, J=7.38 Hz, 1 H) 7.05 - 7.23 (m, 3 H) 7.70 (d, J=6.90 Hz, 1 H) 8.14 (d, J=6.46 Hz, 1 H); LCMS m/z 353.3 (M + H)+, Rt 0.77 min.; HRMS(A) m/z 353.1542 (M + H)+, Rt 1.89 min.
Example 567 FLfN F I NYN ; E F O5;) (S)—3-(2-(1-(2,3-difluorophenyl)ethylamino)f|uoropyrimidinyl)oxazolidinone was prepared using a method similar to that described for the preparation of Example 566. 1H NMR (400 MHz, CD30D) 5 ppm 1.50 (d, J=7.04 Hz, 3 H) 3.91 (br. s., 1 H) 4.09 - 4.20 (m, 1 H) 4.42 - 4.56 (m, 2 H) 5.26 (q, J=6.68 Hz, 1 H) 6.99 - 7.12 (m, 2 H) 7.16 (t, J=7.48 Hz, 1 H) 8.13 (d, J=3.37 Hz, 1 H). HRMS(A) m/z 339.1075 (M + H)+, Rt 1.86 min.
Example 568 2-fluoro-N-(trans—4-hydroxycyclohexyl)—4-((S)—1-(4-((S)isopropyloxooxazolidin yl)pyrimidinylamino)ethyl)benzamide OkN/(jiN FH OWOH Step 1: Preperation of (S)(1-(tert-butoxycarbonylamino)ethy|)fluorobenzoic acid: To (S)—4-(1-aminoethyl)fluorobenzoic acid (900 mg, 4.10 mmol) was added, DCM (11 ml), Hunig's Base (2.147 ml, 12.29 mmol) and BOC-Anhydride (1.998 ml, 8.61 mmol).
Then NMP (11.00 ml) was added to help lity. The reaction was sonicated for 10 minutes and was stirred at room temperature for 22 hours, ed by LCMS. The DCM was mostly concentrated off. Then to the crude on was added 120 ml of water and basified with 10 ml of 5M NaOH. The basic aqueous solution was extracted with 2 x 50 ml of (15% ethyl e in heptane) solution. Then to the basic aqueous solution (with the product) was added 150 ml of ethyl acetate and with stirring acidified with 2M s HCI solution to about pH 3. Then the ethyl acetate was extracted, saved and the acidic water extracted again with 100 ml of ethyl acetate. The organic layers were combined and washed with 0.5M aqueous HCI solution 1 x 40 ml, with water 3 x 40 ml, and concentrated to constant mass to give 1104 mg of (S)—4-(1-(tert- butoxycarbonylamino)ethyl)—2-f|uorobenzoic acid, used as is. LCMS m/z ECG pattern of 269.0 (M+H-15 fragment) and weak 228.0 (M+H-56 fragment) compared to expected 284.0 (M + H)+, Rt 0.72 min.
Step 2: Preperation of tert-butyl (S)—1-(3-f|uoro(trans—4- hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate: To (1-(tert-butoxycarbonylamino)ethy|)fluorobenzoic acid (40.8 mg, 0.144 mmol) was added NMP (0.5 ml), transaminocyclohexanol (41.5 mg, 0.360 mmol), Hunig's Base (0.101 ml, 0.576 mmol) and HATU (110 mg, 0.288 mmol) The on was stirred at room temperature for 6 hours, followed by LCMS. To the reaction was added 0.5 ml of NMP, filtered, purified by prep LC and lyophilized to give 33 mg of tert-butyl (S)—1-(3- (trans—4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate as the TFA Salt.
LCMS m/z 381.1 (M + H)+, Rt 0.70 min.
Step 3: Preperation of 4-((S)aminoethyl)f|uoro-N-(trans—4- hydroxycyclohexyl)benzamide: To utyl (S)—1-(3-f|uoro(trans—4- hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate (33 mg, 0.087 mmol) was added, HCI 4M in Dioxane (2 mL, 8.00 mmol) and MeOH (0.2 ml). The reaction was stirred at room temperature for 1 hour, followed by LCMS. The t was concentrated off to residue to give 4-((S)aminoethyl)f|uoro-N-(trans—4-hydroxycyclohexyl)benzamide in quantitative yield (0.087 mmol) as HCI salt. LCMS m/z 281.1 (M + H)+, Rt 0.33 min.
Step 4: Preperation of 2-fluoro-N-(trans—4-hydroxycyclohexyl)((S)(4-((S) isopropyloxooxazolidinyl)pyrimidinylamino)ethyl)benzamide: To 4-((S)aminoethyl)fluoro-N-((1r,4S)—4-hydroxycyclohexyl)benzamide (0.024 g, 0.087 mmol) was added (S)—3-(2-chloropyrimidinyl)isopropyloxazolidinone (0.034 g, 0.139 mmol), DMSO (0.6 ml) and Hunig's Base (0.053 ml, 0.305 mmol). The reaction was heated at 5 °C for 16 hours or until done by LCMS. The reaction was let cool, 0.5 ml of DMSO added, filtered, purified by prep LC and lyophilized to give 10.1 mg of 2-fluoro-N-(trans—4-hydroxycyclohexyl)—4-((S)(4-((S)isopropyloxooxazolidin yl)pyrimidinylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 486.2 (M + H) +, Rt 0.57 min. 1H NMR (400 MHz, CD30D) 8 ppm 8.13 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 6.7 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.13 - 7.28 (m, 2H), 5.16 (br. s., 1H), 4.67 (br. s., 1H), 4.37 (d, J = 5.5 Hz, 2H), 3.82 (br. s., 1H), 3.53 (d, J = 3.9 Hz, 1H), 1.97 (dd, J = 5.1, 3.1 Hz, 4H), 1.57 (d, J = 7.0 Hz, 3H), 1.38 (t, J = 8.6 Hz, 4H), 0.50 - 0.88 (m, 6H); HRMS(A) m/z 486.2523 (M + H)+.
Example 569 (S)—3-(2-((S)—1-(6-(4-fluorophenoxy)pyridinyl)ethylamino)pyrimidinyl)—4- isopropyloxazolidinone 63*66o | :N To (S)(2-chloropyrimidinyl)isopropyloxazolidinone (28 mg, 0.116 mmol) was added (S)(6-(4-f|uorophenoxy)pyridinyl)ethanamine (46.7 mg, 0.174 mmol), DMSO (0.6 ml) and Hunig's Base (0.071 ml, 0.406 mmol). The on was heated at 105-110 °C for 24 hours or until done by LCMS. The reaction was let cool, 0.5 ml of DMSO was added, filtered, purified by prep LC and lyophilized to give 7.1 mg of (S)—3-(2-((S)(6-(4- fluorophenoxy)pyridinyl)ethylamino)pyrimidinyl)isopropyloxazolidinone as the TFA Salt. LCMS m/z 438.2 (M + H)+, Rt 0.82 min. 1H NMR (400 MHz, CD30D) 8 ppm 8.04 (d, J = 6.3 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.6, 2.3 Hz, 1H), 7.53 (d, J = 6.3 Hz, 1H), 6.94 - 7.10 (m, 4H), 6.84 (d, J = 8.6 Hz, 1H), 5.05 (d, J = 7.0 Hz, 1H), 4.61 (d, J = 3.9 Hz, 1H), 4.28 (d, J = 5.5 Hz, 2H), 1.49 (d, J = 7.0 Hz, 3H), 0.51 - 0.78 (m, 6H); HRMS(A) m/z 46 (M + H)+.
Example 570 (S)—3-(2-((S)—1-(3-fluoro—4-(piperidinecarbonyl)phenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone OiN/E/MJLN F O To -(1-aminoethyl)f|uorophenyl)(piperidiny|)methanone (0.019 g, 0.076 mmol) was added (S)(2-chloropyrimidinyl)isopropyloxazolidinone (0.028 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110 °C for 16 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP was added, filtered, purified by prep LC and lyophilized to give 4.0 mg of (S)- 3-(2-((S)—1-(3-f|uoro(piperidinecarbonyl)phenyl)ethylamino)pyrimidiny|) isopropyloxazolidinone as TFA Salt. LCMS m/z 456.1 (M + H)+, rt 0.74 min. 1H NMR (400 MHz, CD30D)8 ppm 8.13 (d, J = 6.7 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.30 - 7.38 (m, 1H), 7.23 - 7.28 (m, 1H), 7.20 (d, J = 10.6 Hz, 1H), 5.18 (br. s., 1H), 4.63 - 4.74 (m, 1H), 4.33 - 4.42 (m, 2H), 3.61 - 3.79 (m, 2H), 1.61 - 1.76 (m, 5H), 1.57 (d, J = 7.0 Hz, 3H), 1.51 (br. s., 2H), 0.77 (br. s., 3H), 0.62 (br. s., 3H); HRMS(A) m/z 456.2416 (M + H)+.
Example 571 (S)—3-(5-fluoro((S)(3-f|uoro(piperidinecarbonyl)phenyl)ethylamino)pyrimidin yl)isopropyloxazolidinone OKNKKHKNOF / To (S)-(4-(1-aminoethyl)f|uorophenyl)(piperidiny|)methanone (0.019 g, 0.076 mmol) was added (S)(2-chlorofluoropyrimidinyl)isopropyloxazolidinone (0.030 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110 °C for 8 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 4.5 mg of (5- ((S)(3-fluoro(piperidinecarbonyl)phenyl)ethylamino)pyrimidinyl) isopropyloxazolidinone as TFA Salt. LCMS m/z 474.2 (M + H)+, Rt 0.91 min. 1H NMR (400 MHz, CD30D) 8 ppm 8.21 (d, J = 2.7 Hz, 1H), 7.22 - 7.33 (m, 2H), 7.17 (d, J = 11.0 Hz, 1H), 4.97 (q, J = 7.0 Hz, 1H), 4.59 (br. s., 1H), 4.47 (t, J = 8.8 Hz, 1H), 4.20 - 4.32 (m, 1H), 3.68 (br. s., 2H), 1.57 - 1.75 (m, 5H), 1.48 (d, J = 7.0 Hz, 5H), 0.59 (br. s., 3H), 0.52 (br. s., 3H); HRMS(A) m/z 474.2330 (M + H)+.
Example 572 ohexylfluoro—4-((S)—1-(5-fluoro((S)isopropyloxooxazolidinyl)pyrimidin- 2-ylamino)ethyl)benzamide OLNFrNJLN FH To (S)—4-(1-aminoethyl)-N-cyclohexylfluorobenzamide (16 mg, 0.061 mmol) was added (S)(2-chloro—5-fluoropyrimidinyl)isopropyloxazolidinone (31.4 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The on was heated at 125 °C for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 2.5 mg of N-cyclohexyl- 2-fluoro—4-((S)—1-(5-fluoro((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 488.2 (M + H)+, Rt 0.99 min. 1H NMR (400 MHz, CD30D) 8 ppm 8.21 (br. s., 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.24 (dd, J = 8.0, 1.4 Hz, 1H), 7.16 (d, J = 12.1 Hz, 1H), 4.39 - 4.54 (m, 2H), 4.23 (t, J = 7.2 Hz, 1H), 3.83 (t, J = 10.4 Hz, 1H), 1.86 - 1.97 (m, 2H), 1.76 (d, J = 12.9 Hz, 2H), 1.64 (d, J =12.9 Hz, 1H), 1.48 (d, J = 7.0 Hz, 3H), 1.12 - 1.42 (m, 6H), 0.61 (br. s., 6H); HRMS(A) m/z 488.2484 (M + H)+ Example 573 N-cyclohexylfluoro—4-((S)—1-(4-((S)isopropyloxooxazolidinyl)pyrimidin ylamino)ethyl)benzamide OkakN FH To (S)—4-(1-aminoethyl)-N-cyclohexylfluorobenzamide (16 mg, 0.061 mmol) was added (S)(2-chloropyrimidinyl)isopropyloxazolidinone (29.3 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125 °C for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 5.6 mg of N-cyclohexylfluoro -(4-((S)isopropyloxooxazolidinyl)pyrimidinylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 470.2 (M + H)+, Rt 0.83 min. 1H NMR (400 MHz, CD30D) 8 ppm 8.12 (br. s., 1H), 7.57 - 7.73 (m, 2H), 7.13 - 7.27 (m, 2H), 5.15 (br. s., 1H), 4.66 (br. s., 1H), 4.36 (d, J = 5.5 Hz, 2H), 3.76 - 3.94 (m, 1H), 1.87 - 1.99 (m, 2H), 1.77 (d, J = 12.9 Hz, 2H), 1.65 (d, J = 13.7 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.12 - 1.50 (m, 6H), 0.73 (br. s., 3H), 0.62 (br. s., 3H); HRMS(A) m/z 470.2572 (M + H)“ e 574 (S)—4-lsopropyl(2-(((S)—1-(4-(pyrimidinyloxy)pheny|)ethyl)amino)pyrimidin yl)oxazolidinone H OI\N NYN N/J l/N 5 o N To the solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (43 mg, 0.169 mmol) in NMP (0.7 mL) was added (S)(4-(pyrimidinyloxy)phenyl)ethanamine (41 mg, 0.169 mmol) and DIEA (88 uL, 0.507 mmol). The brown reaction mixture was stirred at 110 °C for 2 days. The reaction mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, ed off and concentrated under reduced pressure.
The residue was purified by e phase column chromatography [C-18] to provide (S)—4-isopropyl(2-(((S)—1-(4-(pyrimidinyloxy)phenyl)ethyl)amino)pyrimidin yl)oxazolidinone (7 mg) as its oroacetic acid salt.
MS m/z 421.3 (M + H)+, Rt 0.68 min.
HRMS(A) m/z 421.1996 (M + H)+, Rt 1.54 min.
Example 575 4-Phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)-1,8-dioxaazaspiro[4.5]decan O / N )k l N N N A mixture of crude 3-(2-chloropyrimidiny|)pheny|-1,8—dioxaazaspiro[4.5]decan one (330 mg, 0.954 mmol), (S)phenylethanamine (810 mg, 6.68 mmol), Hunig's base (1.17 mL, 6.68 mmol) in DMA (3.5 mL) was heated in a sealed tube at 80 °C for ~16 hours. The mixture was allowed to cool to room temperature, diluted with DMSO and purified by reverse phase HPLC. Selected fractions were combined and lized, providing 4-phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)—1,8—dioxa azaspiro[4.5]decanone as its trifluoroacetic acid salt as a white solid. LCMS m/z 431.2 (M + H)+, Rt 0.83 min.
The solid was ved in ethyl acetate/saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 solution (2x), brine, dried over sodium sulfate, filtered off and trated under reduced pressure providing 4-phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)—1,8—dioxa azaspiro[4.5]decanone (120 mg).
Examples 576 & 577 phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)-1,8—dioxa azaspiro[4.5]decanone and (R)—4-phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)- 1,8-dioxaazaspiro[4.5]decanone OkN/qLN/kfljo / N 120 mg of 4-phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)—1,8—dioxa ro[4.5]decanone were dissolved in EtOH (10 mL).
Analytical separation: Column: CHIRALPAK AD-H (5 um) 100 x 4.6 mm (Daicel Chemical Industries, LTD.).
Solvent: n-heptane : ethyl alcohol = 70 : 30 Flow rate: 1.0 ; detection: UV = 220 nm.
Fraction 1: Retention time: 5.84 min.
Fraction 2: Retention time: 10.18 min.
Preparative separation: Column: CHIRALPAK AD-prep (10 um) 2 x 25 cm.
Solvent: n-heptane : ethyl alcohol = 70 : 30 Flow rate: 20 mL/min; 530 psi; injection: 4 mL; detection: UV = 210 nm.
Fractions were concentrated under reduce pressure. The residue was dissolved in acetonitrile and filtered h a syringe filter, diluted with water and lyophilized. e 576: Peak 1: white powder. Yield: 52.0 mg; de = 99% (UV, 220 nm).
LCMS m/z 431.3 (M + H)+, Rt 0.81 min.
Example 577: Peak 2: white . Yield: 47.8 mg; de = 99% (UV, 220 nm).
LCMS m/z 431.3 (M + H)+, Rt 0.81 min.
Examples 578 and 579 phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)—2,5-dioxa azaspiro[3.4]octanone and (S)—8-phenyl(2-((S)—1-phenylethylamino)pyrimidinyl)—2,5-dioxaazaspiro[3.4]octan- 6-one were prepared using s similar to those described for the preparation of Example 576 & 577.
Table 23.
Chiral column Chiral column Example Structure for for quality Retention No. separation/. control/ time conditions conditions AD-H column; 578 (Peak AD column; heptane:EtOH 1) 56 mg/ 75:25; 6 mL EtOH; 1 mL/min heptane:EtOH 75:25; AD-H column; 579 (Peak 20 mL/min, heptane:EtOH 2) 400 psi 75:25; 1 mL/min The compounds in Table 24 were prepared using methods similar to those described for the ation of Example 569 Table 24.
Table 25. al name, NMR chemical shifts and LCMS signal for each compound listed in Table 24. 1H NMR 400 MHz 8 ppm 580: (S)(5-fluoro((S)— (CD30D) 0.46 - 0.69 (m, 6 H) 0.81 - 0.91 HRMS(A) luoro (m, 1 H) 1.53 (d, J=3.00 Hz, 3 H) 4.21 - m/z (trifluoromethyl)phenyl)eth 4.29 (m, 1 H) 4.43 - 4.53 (m, 2 H) 5.25 (m, 431.1516 ylamino)pyrimidinyl) J=7.00, 7.00, 7.00 Hz, 1 H) 7.43 (m, (M + H)+; isopropyloxazolidinone J=7.40 Hz, 2 H) 7.52 - 7.59 (m, 1 H) 8.21 - Rt-2.40 8.27 m, 1 H min 581: (S)isopropyl(2- (CD30D) 0.63 - 1.00 (m, 7 H) 4.37 - 4.49 HRMS(A) (4- (m, 2 H) 4.58 - 4.65 (m, 1 H) 4.66 - 4.78 m/z phenoxybenzylamino)pyri (m, 2 H) 6.95 - 7.02 (m, 4 H) 7.10 - 7.16 405.1935 midinyl)oxazolidin (m, 1 H) 7.32 - 7.40 (m, 4 H) 7.75 (d, (M + H)+; one J=7.04 Hz, 1 H) 8.16 (d, J=6.65 Hz, 1 H) Rt-2.02 582: (4S)isopropyl(2- HRMS(A) (1-(4,5,6,7- m/z tetrahyd o[d]thiazol- 388.1814 2-yl)ethylamino)pyrimidin- (M + H)+; 4-yl)oxazolidinone Rt- 1.82/1.88 Examples 583 & 584 (S)isopropyl(2-((R)-1,1,1-trifluoropropanylamino)pyrimidinyl)oxazolidinone (S)isopropyl(2-((S)—1,1,1-trifluoropropanylamino)pyrimidinyl)oxazolidinone .“1Nr”1*F gYVkF To a solution of (S)(2-chloropyrimidinyl)isopropyloxazolidinone (40 mg, 0.166 mmol) in 2-butanol was added 1,1,1-trifluoropropanamine (74.9 mg, 0.662 mmol) and para-toluenesulfonic acid monohydrate (74.9 mg, 0.662 mmol). The mixture was heated under argon in a sealed vial for ~7 days at 115 °C. Independently, to a solution of (S) (2-chloropyrimidinyl)isopropyloxazolidinone (100 mg, 0.414 mmol) in 2-butanol was added 1,1,1-trifluoropropanamine (187 mg, 1.655 mmol) and oluenesulfonic acid monohydrate (157 mg, 0.828 mmol). The e was heated under argon in a sealed vial at 115 °C for ~4 days. The two reaction mixtures was combined and concentrated under reduced pressure. The e was diluted with DMSO and water (~10 vo|.% of DMSO), filtered through a syringe filter and purified by e phase HPLC. Selected fractions were collected and lyophilized providing two isomers as white solids as their trifluoroacetic acid salts. 1st Peak 583: Yield: 29.1mg. 1H NMR (400 MHz, CD30D) 8 ppm 0.90 (d, J=7.04 Hz, 3 H) 0.98 - 1.02 (m, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 2.59 (dtd, J=13.89, 6.95, 6.95, 3.52 Hz, 1 H) 4.43 - 4.47 (m, 2 H) 4.76 - 4.83 (m, 2 H) 7.70 (d, J=5.87 Hz, 1 H) 8.20 (d, J=6.26 Hz, 1 H) LCMS m/z 319.3 (M + H)+, Rt 0.73 min. HRMS(A) m/z 319.1391 (M + H)+, Rt 1.89 min 2nd Peak 584: Yield: 38.5 mg. 1H NMR (400 MHz, CD30D) 8 ppm 0.87 (d, J=7.04 Hz, 3 H) 0.98 (d, J=7.04 Hz, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 2.48 - 2.60 (m, 1 H) 4.40 - 4.49 (m, 2 H) 4.88 - 4.95 (m, 2 H) 7.69 (d, J=5.87 Hz, 1 H) 8.20 (d, J=6.65 Hz, 1 H) LCMS m/z 319.3 (M + H)+, Rt 0.73 min. HRMS(A) m/z 319.1385 (M + H)+, Rt 1.88 min Example 585 (4S)—4-phenyl(2-(1,1,1-trifluoropropanylamino)pyrimidinyl)oxazolidinone 2012/055133 A mixture of (S)—3-(2-chloropyrimidinyl)—4-phenyloxazolidinone (40 mg, 0.145 mmol), trifluoropropanamine (82 mg, 0.725 mmol), Hunig's Base (0.038 mL, 0.218 mmol) in DMSO (0.4 mL) was heated under argon at 115 °C for ~3 days. Then mixture was allowed to cool to room temperature. The mixture was diluted with DMSO and water (~10 vol.% of DMSO), filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing -pheny|— 3-(2-(1,1,1-trifluoropropanylamino)pyrimidinyl)oxazolidinone (ratio of two isomers: 7/3) as white solid as its trifluoroacetic acid salt. LCMS m/z 353.2 (M + H)+, Rt 0.78 min. HRMS(A) m/z 353.1231 (M + H)+, Rt 1.92/1.96 min.
Example 586 (S)—3-(2-((S)—1-cyclopropylethylamino)—5-fluoropyrimidinyl)—4-phenyloxazolidinone Fa”| A mixture of (S)(2-chlorofluoropyrimidinyl)phenyloxazolidinone (40 mg, 0.136 mmol), (S)—1-cyclopropylethanamine (34.8 mg, 0.409 mmol), Hunig's Base (0.119 mL, 0.681 mmol) in DMSO (0.4 mL) was heated under argon at 105-115 0C for ~18 hrs (alternative: 120-135 °C for ~90 min). Then mixture was allowed to cool to room temperature. The mixture was diluted with DMSO and water (~10 vol.% of DMSO), filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lized providing (S)(2-((S)cyc|opropy|ethy|amino) fluoropyrimidinyl)—4-phenyloxazolidinone (26 mg) as a white as its trifluoroacetic acid salt. 1H NMR (400 MHz, CD30D) 8 ppm -0.14 - -0.05 (m, 1 H) 0.01 - 0.08 (m, 1 H) 0.23 - 0.31 (m, 1 H) 0.36 - 0.44 (m, 1 H) 0.78 - 0.86 (m, 1 H) 1.19 (d, J=6.65 Hz, 3 H) 3.05 - 3.14 (m, 1 H)4.25-4.32 (m, 1 H)4.89 -4.90 (m, 1 H)5.77 (t, J=8.61 Hz, 1 H)7.32-7.39 (m, 5 H) 8.15 (d, J=3.52 Hz, 1 H).
LCMS m/z 343.1 (M + H)+, Rt 0.88 min. HRMS(A) m/z 77 (M + H)+, Rt 2.09 min The compounds in Table 26 were prepared using methods similar to those described for the preparation of Example 586.
Table 26.
Table 27. Chemical name, NMR chemical shifts and LCMS signal for each nd listed in Table 26.
Example: Name 1H NMR 400 MHz 8 um 587: (S)(2-((S)—1 - ) -0.55 - -0.27 (m, 1 H), -0.01 (m, MS m/z cyclopropylethylamino)pyr J=9.00, 4.30 Hz, 1 H), 0.12 - 0.32 (m, 1 H) 325.2 (M imidinyl) 0.35 - 0.50 (m, 1 H) 0.64 - 0.93 (m, 1 H) + H)+; Rt- phenyloxazolidinone 1.28 (d, J=1.00 Hz, 3 H) 2.77 - 3.00 (m, 1 0.77 min.
H) 4.26 (dd, J=1.00 Hz, 1 H) 4.76 - 4.95 HRMS(A) (m, 1-2 H; overlay with solvent) 5.75 (dd, m/z J=1.00 Hz, 1 H) 7.17 - 7.52 (m, 5 H) 7.78 325.1664 (d, J=1.00 Hz, 1 H) 8.08 (d, J=7.04 Hz, 1 (M + H)+; H) Rt-1.53 588: (S)(biphenylyl)— (CD30D) 0.01 (m, J=4.30 Hz, 1 H) 0.14 - MS m/z 3-(2-((S) 0.26 (m, 1 H) 0.33 - 0.45 (m, 1 H) 0.73 - 401.3 (M cyclopropylethylamino)pyr 0.85 (m, 1 H) 1.28 (d, J=6.65 Hz, 3 H) 2.91 + H)+; Rt- imidinyl)oxazolidin - 3.02 (m, 1 H) 4.32 (dd, J=9.00, 4.30 Hz, 1 0.89 min. one H) 4.89 - 4.96 (m, 1 H) 5.81 (dd, J=9.00, ) 4.30 Hz, 1 H) 7.34 - 7.42 (m, 3 H) 7.45 (t, m/z J=7.63 Hz, 2 H) 7.59 - 7.84 (m, 2 H) 7.87 401.1988 (m, J=8.20 Hz, 2 H) 7.79 (d, J=7.04 Hz, 1 (M + H)+; H) 8.10 (d, J=7.04 Hz, 1 H) Rt-1.89 589: (S)(2-(1- (CD30D) 0.17 - 0.24 (m, 1 H) 0.31 (dq, HRMS(A) cyclopropylethylamino) J=9.34, 4.71 Hz, 1 H)0.41 -0.55 (m, 2 H) m/z fluorop rimidin l- 0.93-1.04 m, 1 H 1.26 d, J=6.65 Hz,3 464.1125 2012/055133 4,4,5,5- H) 1.42 (s, 6 H) 1.49 (s, 6 H) 3.34 - 3.42 tetramethyloxazolidin (m, 1 H) 8.17 (d, J=3.13 Hz, 1 H) MS m/z one 323.6 (M + H)+; Rt—0.89 min. HRMS m/z 323.1891 M + H +; Rt-2.10 min The compounds in Table 28 were prepared using methods similar to those described for the preparation of Example 568 Table 28.
WO 46136 Table 29. Chemical name, NMR chemical shifts and LCMS signal for each compound listed in Table 28.
Example: Name 1H NMR 400 MHz 5 ppm _ 590: N-cyclopentyl (CD30D) 8.14 (d, J = 6.3 Hz, 1H), 7.72 (d, HRMS(A) fluoro—4-((S)—1-(4-((S) J = 7.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), m/z (M + isopropyloxooxazolidin- 7.13 - 7.31 (m, 2H), 5.17 (br. s., 1H), 4.67 H)+ 3-yl)pyrimidin (br. s., 1H), 4.34 - 4.41 (m, 2H), 4.24 - 4.33 22 ylamino)ethyl)benzamide (m, 1H), 1.99 (dt, J = 11.7, 5.9 Hz, 2H), 1.73 (d, J = 6.7 Hz, 2H), 1.49 - 1.66 (m, 8H , 0.74 br. s., 3H ,0.61 br. s., 3H 591 : N-(4,4- (CD30D) 8.14 (d, J = 6.3 Hz, 1H), 7.70 (d, HRMS(A) difluorocyclohexyl)—2- J = 7.0 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), m/z (M + fluoro—4-((S)—1-(4-((S) 7.12 - 7.32 (m, 2H), 5.16 (br. s., 1H), 4.67 H)+ isopropyloxooxazolidin- (br. s., 1H), 4.37 (d, J = 5.9 Hz, 2H), 4.00 506.2388 3-yl)pyrimidin (t, J = 10.0 Hz, 1H), 1.82 - 2.13 (m, 6H), ylamino)ethyl)benzamide 1.61 - 1.77 (m, 2H), 1.57 (d, J = 7.0 Hz, 3H , 0.73 br. s., 3H ,0.61 br. s., 3H 592: 2-fluoro—4-((S)—1-(4- (CD30D) 8.13 (d, J = 5.9 Hz, 1H), 7.58 - HRMS(A) ((S)isopropyl 7.71 (m, 2H), 7.13 - 7.29 (m, 2H), 5.16 (br. m/z (M + oxooxazolidin s., 1H), 4.67 (br. s., 1H), 4.36 (d, J = 5.5 H)+ imidin Hz, 2H), 4.01 - 4.16 (m, 1H), 3.94 (d, J = 472.2366 ylamino)ethyl)-N- 11.3 Hz, 2H), 3.50 (td, J = 11.7, 2.0 Hz, (tetrahyd ro-2H-pyran 2H),1.82 - 1.94 (m, 2H), 1.59 - 1.69 (m, yl)benzamide 2H), 1.57 (d, J = 7.0 Hz, 3H), 0.73 (br. s., 3H , 0.61 br. s., 3H 593: ro—N-((1R,28)— (CD30D) 8.14 (d, J = 6.3 Hz, 1H), 7.83 (t, J HRMS(A) 2-hyd roxycyclohexyl)—4- = 7.8 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), m/z (M + ((S)(4-((S)isopropyl- 7.14 - 7.36 (m, 2H), 5.15 (d, J = 6.3 Hz, H)+ 2-oxooxazolidin 1H), 4.65 (br. s., 1H), 4.36 (d, J = 5.5 Hz, 486.2526 yl)pyrimidin 2H), 3.96 - 4.05 (m, 1H), 3.94 (d, J = 2.3 ylamino)ethyl)benzamide Hz, 1H), 1.79 (dd, J = 10.4, 4.5 Hz, 1H), 1.69 (d, J = 5.9 Hz,4H), 1.54 - 1.64 (m, 5H), 1.28 - 1.48 (m, 2H), 0.70 (br. s., 3H), 0.60 br. s., 3H 594: - (CD30D) 8.14 (d, J = 6.3 Hz, 1H), 7.69 (d, HRMS(A) dioxidotetrahyd ro-2H- J = 7.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), m/z (M + thiopyranyl)fluoro 7.15 - 7.31 (m, 2H), 5.16 (br. s., 1H), 4.67 H)+ ((S)-1 -((4-((S)isopr0py|- (br. s., 1H), 4.36 (d, J = 5.9 Hz, 2H), 4.13 - 3 2-oxooxazolidin 4.27 (m, 1H), 3.08 (d, J = 13.7 Hz, 2H), yl)pyrimidin 2.25 - 2.36 (m, 2H), 2.07 - 2.24 (m, 2H), yl)amino)ethyl)benzamide 1.57 (d, J = 7.0 Hz, 3H), 0.73 (br. s., 3H), 0.61 br. s., 3H 595: 2-fluoro—N-((1R,2R)— (CD30D) 8.13 (d, J = 6.3 Hz, 1H), 7.63 - HRMS(A) 2-hyd roxycyclohexyl)—4- 7.78 (m, 2H), 7.14 - 7.30 (m, 2H), 5.15 (br. m/z (M + ((S)(4-((S)isopropyl- s., 1H), 4.67 (br. s., 1H), 4.36 (d, J = 5.5 H)+ 2-oxooxazolidin Hz, 2H), 3.67 - 3.83 (m, 1H), 3.38 - 3.51 486.2521 imidin (m, 1H), 2.01 (d, J = 9.0 Hz,2H),1.64 - ylamino)ethyl)benzamide 1.81 (m, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.17 - 1.46 (m, 4H), 0.74 (br. s., 3H), 0.61 (br. s., 3H 596: 2-flu0r0—4- S 4- CD30D 8.14 d, J = 6.7 Hz, 1H , 7.76 d, HRMS A ((S)isopropy|—2- J = 7.4 Hz, 1H), 7.32 - 7.42 (m, 1H), 7.17 - m/z (M + oxooxazolidin 7.31 (m, 2H), 5.22 (br. s., 1H), 4.60 - 4.76 H)+ y|)pyrimidin (m, 2H), 4.33 - 4.44 (m, 2H), 4.02 (dd, J = 486.2528 o)ethy|)—N-methy|— 11.3, 4.3 Hz, 1H), 3.91 (d, J = 8.6 Hz, 1H), N-(tetrahydro—2H-pyran 3.45 - 3.65 (m, 2H), 3.07 - 3.21 (m, 1H), y|)benzamide 2.99 (s, 1H), 2.80 (s, 2H), 1.81 - 2.05 (m, 3H), 1.52 - 1.71 (m, 5H), 0.78 (br. s., 3H), 0.63 br. s., 3H 597: 2-fluoro—4-((S)—1-(4- (CD30D) 8.14 (d, J = 7.0 Hz, 1H), 7.75 (d, HRMS(A) ((S)isopropy|—2- J = 7.0 Hz, 1H), 7.32 - 7.43 (m, 1H), 7.13 - m/z (M + oxooxazolidin 7.31 (m, 2H), 5.20 (br. s., 1H), 4.70 (br. s., H)+ y|)pyrimidin 1H), 4.33 - 4.45 (m, 2H), 3.09 (s, 3H), 2.92 416.2106 y|amino)ethy|)—N,N- (d, J = 0.8 Hz, 3H), 1.76 (br. s., 1H), 1.59 dimethylbenzamide (d, J = 7.0 Hz, 3H), 0.78 (br. s., 3H), 0.62 598: (S)(2-((S)—1-(3- (CD30D) 8.14 (d, J = 6.7 Hz, 1H), 7.73 (d, HRMS(A) fluoro—4-(morpholine—4- J = 6.7 Hz, 1H), 7.35 - 7.43 (m, 1H), 7.28 m/z (M + carbonyl)pheny|)ethylamin (d, J = 7.8 Hz, 1H), 7.22 (d, J = 10.6 Hz, H)+ o)pyrimidinyl)—4- 1H), 5.18 (br. s., 1H), 4.69 (br. s., 1H), 4.30 458.2209 isopropyloxazolidinone - 4.42 (m, 2H), 3.73 (d, J = 3.1 Hz, 4H), 3.59 (t, J = 4.7 Hz, 2H), 1.58 (d, J = 7.0 Hz, 3H , 0.76 br. s., 3H ,0.62 br. s., 3H 599: (S)(2-((S)—1-(3- ) 8.14 (d, J = 6.7 Hz, 1H), 7.76 (d, HRMS(A) —4-((R)—3- J = 7.0 Hz, 1H), 7.36 (d, J = 6.7 Hz, 1H), m/z (M + methylmorpholine—4- 7.14 - 7.31 (m, 2H), 5.20 (br. s., 1H), 4.70 H)+ carbonyl)pheny|)ethylamin (br. s., 1H), 4.65 (br. s., 1H), 4.34 - 4.45 472.2366 o)pyrimidinyl)—4- (m, 2H), 4.29 (d, J = 13.3 Hz, 1H), 3.96 (d, isopropyloxazolidinone J = 10.6 Hz, 1H), 3.75 (d, J = 11.3 Hz, 1H), 3.51 - 3.67 (m, 2H), 3.43 - 3.51 (m, 1H), 3.07 - 3.19 (m, 1H),1.76(br.s., 1H),1.59 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 6.7 Hz, 2H), 1.28 (br. s., 1H), 0.77 (br. s., 3H), 0.62 600: (S)(2-((S)—1-(3- (CD30D) 8.14 (d, J = 6.7 Hz, 1H), 7.73 (d, HRMS(A) fluoro—4-(4- J = 7.0 Hz, 1H), 7.31 - 7.40 (m, 1H), 7.16 - m/z (M + hydroxypiperidine—1- 7.29 (m, 2H), 5.18 (br. s., 1H), 4.70 (br. s., H)+ carbonyl)pheny|)ethylamin 1H), 4.31 - 4.45 (m, 2H), 4.16 (dd, J = 472.2369 o)pyrimidinyl)—4- 12.9, 5.5 Hz, 1H), 3.87 (br. s., 1H), 3.48 (d, isopropyloxazolidinone J = 14.1 Hz, 1H), 3.35 (d, J = 3.5 Hz, 1H), 3.05 - 3.22 (m, 1H), 1.85 - 1.98 (m, 1H), 1.70 - 1.83 (m, 2H), 1.58 (d, J = 7.0 Hz, 3H), 1.49 - 1.55 (m, 1H), 1.43 (br. s., 1H), 0.76 br. s., 3H , 0.62 br. s., 3H 601: (S)(2-((S)—1-(3- (CD30D) 8.13 (d, J = 6.7 Hz, 1H), 7.70 (d, HRMS(A) —4-(4- J = 6.7 Hz, 1H), 7.31 - 7.41 (m, 1H), 7.26 m/z (M + methoxypiperidine—1- (d, J = 7.8 Hz, 1H), 7.21 (d, J = 10.6 Hz, H)+ carbonyl)pheny|)ethylamin 1H), 5.17 (br. s., 1H), 4.69 (br. s., 1H), 4.33 23 o)pyrimidinyl)—4- - 4.42 (m, 2H), 3.98 (dd, J = 10.8, 6.5 Hz, isopropyloxazolidinone 1H), 3.40 - 3.60 (m, 3H), 3.34 (s, 3H), 3.18 (d, J = 8.6 Hz,1H), 1.88 - 2.03 (m, 1H), 1.79 (br. s., 1H), 1.62 (br. s., 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.49 (br. s., 1H), 0.76 (br. s., 3H , 0.62 br. s., 3H 602: (S)(2-((S)—1-(3- (CD30D) 8.14 (d, J = 6.7 Hz, 1H), 7.73 (d, ) fluoro—4- 4- J = 7.0 Hz, 1H - 7.44 , 7.34 m, 1H ,7.16 - m/z M + fluoropiperidine 7.31 (m, 2H), 5.18 (br. s., 1H), 4.93 (br. s., H)+ carbonyl)phenyl)ethylamin 1H), 4.70 (br. s., 1H), 4.29 - 4.43 (m, 2H), 474.2324 o)pyrimidinyl)—4- 3.91 (d, J = 11.3 Hz, 1H), 3.70 (br. s., 1H), isopropyloxazolidinone 3.40 - 3.53 (m, 1H), 1.93 - 2.06 (m, 1H), 1.83 - 1.93 (m, 2H), 1.77 (dd, J = 10.2, 4.7 Hz, 2H), 1.58 (d, J = 7.0 Hz, 3H), 0.76 (br. s., 3H , 0.62 br. s., 3H 603: (S)(2-((S)—1-(3- (CD30D) 8.13 (d, J = 8.7 Hz, 1H), 7.72 (d, HRMS(A) fluoro((R)—3- J = 7.0 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), m/z (M + hydroxypiperidine 7.14 - 7.30 (m, 2H), 5.19 (br. s., 1H), 4.70 H)+ carbonyl)phenyl)ethylamin (br. s., 1H), 4.30 - 4.44 (m, 2H), 3.71 (br. 472.2362 o)pyrimidinyl)—4- s., 1H), 3.38 - 3.52 (m, 1H), 3.08 - 3.19 (m, isopropyloxazolidinone 1H), 3.02 (br. s., 1H), 1.98 (br. s, 1H), 1.87 (br. s., 1H), 1.88 - 1.81 (m, 1H), 1.49 - 1.82 (m, 5H), 1.43 (br. s., 1H), 0.78 (br. s., 3H), 0.63 br. s., 3H 604: (S)(2-((S)—1-(3- (CD30D) 8.13 (d, J = 6.3 Hz, 1H), 7.71 (d, HRMS(A) fluoro(pyrrolidine J = 7.0 Hz, 1H), 7.34 - 7.43 (m, 1H), 7.14 - m/z (M + carbonyl)phenyl)ethylamin 7.30 (m, 2H), 5.18 (br. s., 1H), 4.70 (br. s., H)+ o)pyrimidinyl)—4- 1H), 4.28 - 4.43 (m, 2H), 3.57 (t, J = 6.8 442.2263 isopropyloxazolidinone Hz, 2H), 1.93 - 2.07 (m, 2H), 1.83 - 1.93 (m, 2H), 1.58 (d, J = 7.0 Hz, 3H), 0.77 (br. s., 3H , 0.63 br. s., 3H Biological Data Mutant IDH1 biochemical assay: LC-MS detection of 2-HG.
Mutant IDH1 R132H catalytic activity was monitored using the quantitative liquid chromatography/mass spectrometry ) detection of 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.
More ically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Costar, Cat. No. 781201) using a final reaction volume of 30 0L and the ing assay buffer conditions: 50 mM HEPES pH 7.4, 10 mM MgClz, 50 mM KCI, 1 mM DTT, 0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.
The final reaction mixture contained 3.3% DMSO and inhibitors with concentrations ranging 0.02 — 50 0M. The IDH1 enzyme was used at a final concentration of 0.25 nM. Following 45 minutes incubation, the reaction mixtures were quenched by the addition of 10 uL of 16% formic acid containing 800 nM of 5-carbon d HG). The protein was then precipitated by the addition of 2.5 volumes of acetonitrile followed by centrifugation (3000 x g, 20 minutes). The tration of 2-HG in the resulting atants was ed by LC-MS (see below).
LC-MS method. Reaction mixture supernatants were submitted to tographic separation on a BiobasicAX column (2.1 mm x 20 mm, 5 gm particle, Thermo Scientific Inc.) The chromatographic mobile phases were A) 25 mM ammonium bonate and B) acetonitrile (0.1% ammonium hydroxide). Nicotinamide was eluted at 1 ml/min using a 85-5% B gradient over 0.9 minutes (Agilent 12OOSL LC , Thermofisher LX—4 autosampler) and analyzed by multiple reaction monitoring (MRM) on a API4000 QTrap mass spectrometer (ABSciex, Framingham, MA) in the positive electrospray ionization (ESI+) mode. The mass transition for 2-HG and 13CHG were 1479129 and 1529134, respectively. The ve responses (2-HG/13CHG) were measured at varied tor trations and used to calculate inhibitory |C50 values (normalized |C50 regression curves).
R132 protein sion and purification.
IDH1 R132H was cloned into the pET47b vector using the restriction sites Xmal/Xhol which yields an in frame, N-terminal His5 site cleavable with ssion protease. This plasmid was transformed into RosettaTM 2(DE3) (Novagen) cells. In shake flasks, 8L of cells were grown in Terrific Broth (Teknova) (plus kanamycin L and chloramphenicol 34ug/mL) at 37°C to an ODGOO of 0.8 and protein expression was induced by addition of IPTG to a concentration of 0.20mM. The cells were subsequently grown for 18 hours at 18°C.
Hiss-IDH1 ) Uncut protein MAHHHHHHSAALEVLFQGPGMSKKISGGSWEMQGDEMTRIIWELIKEKLIFPYVELDL HSYDLGIENRDATNDQVTKDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGT |RNILGGTVFREAIICKNIPRLVSGWVKPIIIGHHAYGDQYRATDFWPGPGKVEITYTPSD GTQKVTYLVHNFEEGGGVAMGMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKK YDGRFKDIFQEIYDKQYKSQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDV QSDSVAQGYGSLGMMTSVLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIF AWTRGLAHRAKLDNNKELAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNT FEFMDKLGENLKIKLAQAKL (stop) (SEQ ID NO: 1) IDH1 (R132H) Prescission Cut Protein (N-term gpg is cloning artifact) GPGMSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVT KDAAEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIP RLVSGWVKPI||GHHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGG VAMGMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYK SQFEAQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTS VLVCPDGKTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKE WO 46136 LAFFANALEEVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQA KL (stop) (SEQ ID NO: 2) Purification The cells were nized in Lysis Buffer with protease inhibitors (cOmpIete EDTA-free protease inhibitor tablets (Roche), 1 tablet per 50mL of buffer), DNAse, and to 200 pM PMSF and lysed in a Microfluidizer. After lysis, Triton X—100 was added to 0.1% and stirred at 4°C for 30 minutes.
The cleared lysate was loaded onto 2 x 5mL HisTrap FF crude columns (GE), washed extensively with Lysis Buffer until the A280 stabilized and eluted with Ni n Buffer. Peak eluted fractions were concentrated to 30mL, EDTA was added to 1mM and GST-Prescission protease was added to 3U/100pg of protein. The sample was dialyzed t 2L Dialysis Buffer l (MWCO 50kDa) for 6 hours at 4°C then dialyzed against 2L of Dialysis Buffer II for at least 6 more hours. GST-Prescission cleaved sample was rocked with Glutathione Agarose Beads, spun down and then the supernatant was loaded through a 5mL HisTrap HP column and the flow through was collected.
Flow through was then diluted with ice cold 20mM Tris pH 7.4 and 1mM TCEP until the conductivity d to less than 5 mS/cm (a roughly three fold on). This sample was then flowed through a HiTrap Q column and the flow through was concentrated to 10mL and loaded onto an brated 26/60 Superdex 200 column using SEC Buffer as the mobile phase. Peak fractions were collected, concentrated and aliquoted.
Lysis Buffer: 50mM Tris pH=7.4, 500mM NaCl, 20mM lmidazole, and 1mM TCEP Ni Elution Buffer: 50mM Tris pH=7.4, 150mM NaCl, 200mM lmidazole, and 1mM TCEP Dialysis Buffer l: 20mM Tris pH=7.4, 150mM NaCl, 1mM TCEP, and 50mM lmidazole Dialysis Buffer ll:20mM Tris pH=7.4, 150mM NaCl, and 1mM TCEP SEC Buffer: 20mM Tris pH=7.4, 150mM NaCl, and 1mM TCEP The results of the mutant lDH1 mical assay (mlDH R132H) are given in Table 30.
Some of the examples were run in the assay multiple times and therefore the |C50 values are expressed as a range of activity.
WO 46136 Fluorescence mical assay The |DH1 (R132H) mutant catalyzes the reduced form of NADP+ (NADPH) and d-ketoglutarate (or-KG) to form nicotinamide adenine dinucleotide ate (NADP+) and R (-)hydroxyglutarate (2HG). The reaction can be monitored cally by following the oxidation of NADPH to NADP+ which is measured using fluorescence, excitation at 355 nm and emission at 530 nm. Reactions were monitored using the Perkin-Elmer Envision, Model 2101. More specifically, the biochemical ons were performed at room temperature in 384-well Greiner flat-bottom plates (Cat. No. 781076) using a final reaction volume of 20 HL and the following assay buffer conditions: 50 mM HEPES pH 7.5, 10 mM MgClZ, 1 mM DTT, 0.02% BSA, 0.02% Tween-20, 10 MM NADPH and 100 uM oc-KG. The final reaction mixture contained 2.5% DMSO and test compounds with concentrations ranging 008 — 25 uM. The |DH1 (R132H) enzyme was used at a final concentration of 10 nM. Curve fitting for dose response IC50 determinations was done in the Helios module of the software package DAVID. The 4- parameter logistic model was used: y = min + ((max - min)/ 1 + (x/ IC50)S'°pe) Table 30. Results of the LC-MS and fluorescence biochemical assays.
Example Number LC-MS Fluorescence biochemical biochemical assay IC50 (pM) assay IC50 (uM) WO 46136 WO 46136 53 3.852 58 >50 WO 46136 89 0.203 0.308 92 0.598 3.184 0.207 0.352 0.352 1.918 3.445 2012/055133 125 1.012 0.549 — 0.615 0.089 0.114-0.181 0.095 0.390 — 0.512 2012/055133 6.502 0.009—0.035 0.020-0.043 2012/055133 .05 0.108—0.183 0.079—0.146 0.113 0.0662 0.072 0.0415 0.147 > 50 0.039 0.372 0.877 0236-0316 0221-027 0.108 <0.022 0.152 2012/055133 0.467 0.414-0.975 WO 46136 .718 0.115 WO 46136 33.589 > 25 1.642 4.53 4.37-11.9 23.3 1.06 > 25 WO 46136 2.321 3.27-4.33 > 25 0.839 0.349 .16 0.107 22.5 4.74 .6 4.37 —2.35-5.33 0355-0697 401 19 402 0.39 403 > 25 404 0.964 405 21.1 406 1.82 408 0.237 0.349 0.340 - 0.440 0098-0521 413 21.616 414 .32 421 > 25 422 3.81 423 14.8 424 0491-0747 425 2.45 426 0019-0058 427 2.09 428 > 25 429 9.78 430 0.0908 431 0.811 432 0.0448 433 5.31 434 2.19-3.96 435 —> 25 436 0364-0373 437 —2.69-3.18 —> 25 —6.155 0105-0122 163-106 0.225 0.0414 0.0266 2.46 0.039 WO 46136 0.034 0.0373 .43 0.062 0.0518 2-87 0.020-0.055 —0-164 0-821 —9-82 —3.03-11.8 0.185-0.198 0-78 —14-8 0.0986 0.355 WO 46136 WO 46136 0.123 0.363 0.080 0.053-0.321 0.23 0.085 0.108—0.183 0.00835 —0.00812 0.0477 0.246 0.237 0.283 0.552 0.364 0.04 0.0501 0.161 0.0781 0.00786 0.324 1.91 2.37 1.65 1.07 0.591 0.193 0.432 0.204 > 25 .6 1.02 1.95 0.85 2.92 0006-0009 0.018 IDH Cellular Assay The IDH cellular assay consists of two y-side comparator assays: 1) 2HG oncometabolite ion assay using LC-MS (See Mutant |DH1 biochemical assay for LC-MS detection details) and 2) Cell proliferation assay to monitor off-target killing of cells and to ize 2HG level . |DH1 cellular screens were run with the HOT- 116 cell line (express nous level of |DH1mut R132H, available from Horizon eries X—Man isogenic human cell lines, catalog # HD104-013). The cells were grown in DMEM (LONZA Cat# 12—540F) with 10% Fetal bovine serum (Gibco cat# 10099) and 1X non-essential amino acids (NEAA LONZA cat# 13-114E). Panel assays were run periodically to test compound activity in cell lines with different endogenous mutations — HT1080 (|DH1mut R1320, EMEM + 10% FBS), SNU-1079 (|DH1mut R1320, RPMI + 10%FBS + 1% sodium pyruvate), and SW1353 (lDH2mut R1728, RPMI + 10%FBS + 1% sodium pyruvate).
The assay process is as follows: Day 1: cells were seeded in 384-well plates (Corning Cat# 3707) in triplicates for both the cell proliferation and 2HG assay, and incubated at 37C, 95% Rh, 5% COZ overnight.
Day 2: compounds were serially diluted 1:3 (10 point dilution from 10mM solutions in DMSO) and delivered to the cell assay plates via acoustic dispenser, with final concentration ranging from 30uM to 1.5nM. The plates were returned to the incubator after treatment and ted for 48 hours.
Day 4 Proliferation assay: CTG (cell titer-glo, Promega part # 67558) was added to the assay plates and luminescence signal was read on the plate reader.
Day 4 2HG assay : Extraction sample preparation consisted of aspirating all media from the assay plates, adding 70 ul of 90% methanol in water, dry ice incubation for 15 minutes, centrifuging at 2000 rpm for 30 min to ensure all ulates have d, and transferring 30 ul of the supernatant into LC-MS ready plates. LC-MS analysis follows.
Certain compounds of the invention have been tested in the IDH Cellular Assay. 2012/055133

Claims (18)

CLAIMS What is claimed is:
1. A nd of formula (I) N \ 0 wherein: R1 and R2 are each independently hydrogen, deuterium, halo, hydroxyl, NH2, aryl, aryl, or optionally substituted C1_4 alkyl, wherein said C1_4 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, and NH2; R38' is hydrogen, deuterium, 01-6 alkyl, phenyl, or benzyl and R3b is hydrogen, deuterium, or 01-6 alkyl; or R33 and R3b are joined together forming an ally substituted 3-7 membered lkyl ring or an optionally substituted 4-7 membered heterocyclic ring, n said cycloalkyl and heterocyclic rings are each optionally tuted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl; R48' is hydrogen, 01-6 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene, wherein said phenyl, benzyl, and heteroaryl rings are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_4 alkoxy, C1_3 haloalkyl, C1_3 koxy, 01-6 alkyl, 03-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, -COORb, -802Rb, -NHC(O)Rb, and -NRbRb and R4b is hydrogen, deuterium, or 01-3 alkyl; or WO 46136 R48' and R4b are joined together forming an optionally substituted 3-7 membered cycloalkyl ring or an optionally substituted 4-7 membered cyclic ring, n said cycloalkyl and heterocyclic rings are optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and 01-3 alkyl, provided that only one of R33 and R3b and R48' and R4b are joined together forming a ring; R58 is en or deuterium; R5b is hydrogen, deuterium, methyl, ethyl, CD3, CF3, CH2F, or CHF2 and R6 is optionally substituted 01-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted 03-10 cycloalkyl, wherein said 01-6 alkyl is optionally substituted with one substituent selected from the group consisting of hydroxyl, C1_3 alkoxy and —ORa, n said aryl, heteroaryl, heterocyclic and 03-10 cycloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo; hydroxyl; cyano; nitro; C1_4 alkoxy; C1_3 haloalkyl; C1_3 haloalkoxy; 01-6 alkyl; 03-6 cycloalkyl optionally substituted with one to three substituents each independently selected from the group ting of: hydroxyl, cyano, C1_3 alkyl, C1_3 alkoxy, and 01-3 haloalkyl; phenyl optionally substituted with one to three tuents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1_3 alkoxy, C1_3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, phenoxy, -COORb, -802Rb, -NHC(O)Rb, and NRbRb; 5-6 ed heteroaryl optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, 01-3 alkyl, 01-3 alkoxy; 5-6 membered heterocyclic optionally tuted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, oxo, NH2, and C1_3 alkyl; -CH2Ra; -ORa; -C(O)Ra; -NRaRb; -COORa; —802Ra; —sosz; -NHC(O)Ra; -NHC(O)Rb; —C(O)NRaRb ; -C(O)NHRb; and -SOZNRbRb; or R5b and R6 are joined together forming an optionally substituted 03-7 cycloalkyl group or an ally substituted group of formula (a): (a), wherein n is 1, 2, or 3 and said 03-7 cycloalkyl and group of formula (a) are optionally substituted with one to three substituents each ndently selected from the group consisting of: halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, 01-6 alkyl, 03-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, benzyloxy, , —sozRQ-NH0«»Rhemd-NRbRQ each R8 is independently optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted 03-7 lkyl, n said phenyl and heteroaryl are optionally substituted with one to three substituents each independently ed from the group consisting of halo, hydroxyl, cyano, nitro, 01-3 alkoxy, 01-3 kyl, 01-3 haloalkoxy, and 01-3 alkyl, wherein said heterocyclic is optionally substituted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, C1_3 alkoxy, C1_3 haloalkyl, C1_3 haloalkoxy, C1_4 alkyl, 03-5 cycloalkyl, -C(O)Rb, and —NRbRb,and n said C3_7 cycloalkyl is optionally tuted with one to three substituents each independently selected from the group consisting of halo, hydroxyl, oxo, 01-3 alkoxy, 01-3 haloalkyl, 01-3 haloalkoxy, and 01-3 alkyl; and each Rb is independently hydrogen or 01-6 alkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 of the formula (III) fell/LRa MR R4b R3 (III), or a pharmaceutically acceptable salt thereof.-.
3. The compound ing to claim 2 of the formula (IV) 9,”. R5a R‘4a\\\‘ (IV); or a pharmaceutically acceptable salt thereof.
4. The nd according to claim 3 wherein R33 and R3b are both hydrogen; or a ceutically acceptable salt thereof.
5. The compound according to claim 4 n R58' is hydrogen and R5b is hydrogen, methyl, ethyl, or CF3; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 wherein R5b is methyl; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 wherein R1 is hydrogen, fluoro or chloro and R2 is hydrogen, fluoro, chloro, or methyl; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 wherein R1 and R2 are both hydrogen; or a pharmaceutically acceptable salt thereof.
9. The compound ing to claim 8 wherein R48' is hydrogen, 01-6 alkyl, optionally tuted phenyl, optionally substituted benzyl, optionally substituted heteroaryl, or methylene-dibenzene, wherein said , benzyl, and heteroaryl rings are optionally tuted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, C1-3 , C1-3 haloalkyl, C1-3 haloalkoxy, C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered cyclic, phenoxy, -COOR b, -SO b,- NHC(O)Rb, and- NRbRb 2R and R4b is en or C1-3 alkyl; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 wherein R4b is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
11. The compound according claim 10 wherein R4b is hydrogen; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 wherein R4a is hydrogen, methyl, ethyl, isopropyl, phenyl, 4-fluorophenyl, 4-methoxyphenyl, biphenyl, benzyl, or pyridinyl; or a pharmaceutically able salt thereof.
13. The compound according to claim 12 wherein R4a is isopropyl; or a pharmaceutically acceptable salt thereof.
14. The nd according to any one of claims 1-13 wherein R6 is methyl, C5-10 cycloalkyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted lyl, optionally tuted pyrazolyl, optionally substituted 5 thiazolyl, optionally substitued 1,3,4-oxadiazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substitued isoxazolyl, thienyl, oxazolyl, quinolinyl, optionally substituted benzimidazolyl, benzthiazolyl, benzoxazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[2,1- b][1,3,4]thiadiazolyl, optionally substituted piperidinyl, optionally substituted piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted tetrahydro-thiopyran1,1- 10 dioxide, 1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydro-benzo[1,4]dioxinyl, 8-tetrahydro- [1,2,4]trazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydro-benzothiazolyl, indolizinyl, cyclopropyl, cyclopentyl, or cyclohexyl, n said phenyl, pyridinyl, pyrimidinyl, zinyl, pyrazinyl, triazolyl, pyrazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, olyl, benzimidazolyl, piperidinyl, piperazinyl, and ydro-thiopyran1,1-dioxide are each 15 optionally tuted with one or two substituents as defined in formula (I).
15. The compound according to claim 14 wherein R6 is optionally substituted with one or two substituents each independently selected from the group consisting of: halo; hydroxy; nitro; C1_4 alkoxy; 01-3 haloalkyl; 01-3 haloalkoxy; 01-6 alkyl; 03-6 cycloalkyl optionally substituted with one substituent selected from the group consisting of: cyano, C1_3 alkyl, and C1_3 alkoxy; phenyl optionally substituted with one or two substituents each ndently selected from the group consisting of: fluoro, chloro, methyl, cyano, and methoxy; and 5-6 membered heteroaryl optionally substituted with one or two methyl groups; or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 15 wherein R6 is optionally substituted 1,3,4- oxadiazolyl or optionally substituted 1,2,4-oxadiazolyl; or a pharmaceutically able salt thereof. 15
17. The compound according to claim 14 n R6 is substituted with one -CH2Ra, —C(O)Ra, -NHC(O)R3, -NHC(O)Rb, -C(O)NHRa, C(O)NHRb, -0Ra, -NRaRb, —SOZNRbRb, , or -802Rb group; or a pharmaceutically acceptable salt f.
18. The compound ing to claim 17 wherein R8' is 20 (a) phenyl optionally substituted with one or two substituents each independently selected from the group consisting of , chloro and bromo; (b) optionally substituted 5-6 membered heteroaryl; (c) 05.7 lkyl optionally substituted with one or two substituents each independently selected from the group consisting of fluoro, hydroxy, , and C1
NZ624040A 2011-09-27 2012-09-26 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh NZ624040B2 (en)

Applications Claiming Priority (3)

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US201161539553P 2011-09-27 2011-09-27
US61/539,553 2011-09-27
PCT/IB2012/055133 WO2013046136A1 (en) 2011-09-27 2012-09-26 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh

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NZ624040A NZ624040A (en) 2016-01-29
NZ624040B2 true NZ624040B2 (en) 2016-05-03

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